Complications of cirrhosis


Portal vein thrombosis (PVT) in compensated cirrhosis: A prospective cohort study on 898 patients

Filipe G. Nery1, 2, Cendrine Chaffaut3, 4, Bertrand Condat5, Emmanuelle de Raucourt6, Larbi Boudaoud6, Pierre-Emmanuel Rautou1, 10, Aurelie Plessier1, 10, Dominique Roulot7, 8, Jean Claude Trinchet9, 7, Dominique Valla1, 10, Sylvie Chevret3, 4

1Service d΄Hépatologie, Hôpital Beoujon, Paris, France; 2Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto, Porto, Portugal; 3DBIM, Hôpital Saint-Louis, Paris, France; 4UMR 717, Inserm, Universite Paris Diderot, Paris' France; 5Service d΄Hépato-gastroentérologie, Hôpital Saint-Camille, Bry-sur-Marne, France; 6Service d΄Hématologie Biologique, Hôpital Beaujon, Paris, France; 7UFR SMBH, Université Paris 13 Paris-Nord, Bobigny, France; 8Unité d΄Hépatologie, Hôpital Avicenne, Bobigny, France; 9Service d΄Hpato-gastroentérologie, Hôpital Jean Verdier, Bondy, France; 10Université Paris 7, Clichy, France

The causes and consequences of PVT in cirrhosis, mostly studied in advanced cases, remain unclear. This study aimed to assess prospectively, in patients with Child-Pugh A cirrhosis, (a) the reported risk factors for PVT development; and (b) the impact of PVT on the course of cirrhosis. This is a preplanned satellite study of a reported randomized trial of 3 vs 6 months as a screening interval for hepatocellular carcinoma (HCC) with Doppler ultrasonography, using a protocoled questionnaire for PVT (Trinchet, JC et al. Hepatology 2011). PVT cases developing within 6 months of a diagnosis of HCC were excluded. Aggravation was defined as a composite outcome including ascites, or prothrombin time < 45%, or bilirubin > 45μmol, or albumin < 28g/l, or creatinine > 115μmol/l, or hepatic encephalopathy. Multivariate Cox models were used to assess the cause-specific hazards of (a) PVT, including baseline, and time dependent (portal vein blood flow velocity, and aggravation prior to PVT) variables; and (b) aggravation, including baseline, and time dependent (PVT) variables. A total of 898 Child-Pugh A patients with cirrhosis of mixed etiology and a patent portal vein were followed-up a mean of 47 months. PVT developed in 101 patients, causing partial, complete, and variable obstruction in 82, 10 and 9 patients, respectively. The 5yr cumulative incidence of PVT was 11.9% (95%CI 9.6-14.2). An aggravation occurred in 221 patients (without, before, together with, and after PVT in 178, 14, 4, and 25, respectively), while 58 had PVT without aggravation. (a) Multivariate analysis showed an association of PVT development with baseline size of esophageal varices (p=0.004) and bilirubin (p=0.0007), but not with factor V or factor II gene mutations, or causes for liver disease, or aggravation prior to PVT. Results were similar for partial and complete obstruction. (b) By multivariate analysis, aggravation was associated with baseline age (p=0.004), size of esophageal varices (p=0.0004), creatinine (p<0.0001) and prothrombin time (p<0.0001), and with occurrence of PVT at any time prior to aggravation (1.65, 95%CI 1.03-2.65, p=0.038), but not with PVT occurring less than 6 months prior to aggravation. Conclusion: Development of PVT in compensated cirrhosis is related to subtle features of more severe disease at baseline but not a direct result of cirrhosis progression. Although PVT carries independent prognostic value for a poorer outcome, it is not a direct cause for aggravation. These data point to PVT and aggravation as discrete consequences of a common determinant for progression of cirrhosis, e. g. hepatic or intestinal microcirculatory dysfunction.


Dominique Valla - Board Membership: Sequana Medical; Independent Contractor: IRIS; Speaking and Teaching: Mayoly Spindler, MSD, Janssen Pharmaceuticals

The following people have nothing to disclose: Filipe G. Nery, Cendrine Chaffaut, Bertrand Condat, Emmanuelle de Raucourt, Larbi Boudaoud, Pierre-Emmanuel Rautou, Aurelie Plessier, Dominique Roulot, Jean Claude Trinchet, Sylvie Chevret


Acute kidney injury (AKI) in patients with Acute on Chronic Liver failure (ACLF) is different from patients with cirrhosis

Rakhi Maiwall1, Suman Kumar2, Chitranshu Vashishtha1,Manoj Kumar1, Hitendra K. Garg1, Sumanlata Nayak3, Sunil Taneja1, Bhaskar Thakur2, Shiv K. Sarin1

1Hepatology, ILBS, New Delhi, India; 2Hematology, AIIMS, N. Delhi, India; 3Nephrology, ILBS, N. Delhi, India

Background and Aims: The current definitions for AKI and Hepatorenal syndrome (HRS) have been derived from patients with cirrhosis (CLD). There is paucity of data on AKI in patients with ACLF. We investigated the prevalence, spectrum, natural history and outcome of AKI in patients with ACLF [Asian Pacific Association for Study of Liver, (APASL), definition] and compared it with a cohort of hospitalized patients with cirrhosis. We also compared outcome and response to terlipressin in HRS (International Ascites Club) in both the groups. Methods: AKI was defined according to Acute Kidney Injury Network (AKIN )criteria. Serial creatinine until improvement or upto day 30 was recorded for all patients. Results: Patients with AcLF (n=534) were predominantly males (p<0.0001), younger (p<0.0001) with higher serum bilirubin (p<0.0001), INR (p<0.0001), hepatic encephalopathy (p<0.0001), GI bleed (p<0.0001) and mortality (p<0.0001) as compared to CLD (n=2083). AKI at baseline was significantly more common in patients with ACLF (50.5% vs. 32.3%; p<0.0001) and associated with increased risk of mortality (59.9% vs. 41.3%; p<0.0001) as compared to CLD. A significant difference was also observed in the spectrum of AKI (p<0.0001) with sepsis related AKI as commonest cause in ACLF (160; 58.8%) and prerenal (289; 43%) in CLD. Presence of ACLF (vs CLD) was associated with a six-fold increased risk of AKI (p<0.0001, OR 95% CI 4.9-8.3) on multivariate analysis. There was no significant difference seen in the AKIN stage at baseline (Stage 1 : 61% vs 69%; Stage 2: 29.5% vs 23.5%; Stage 3: 9.9% vs 8.5%), decrease in serum creatinine at 48 hours (67.3% vs 65.3%) and in the overall progression of AKI (48.5%vs 45.1%), however, requirement of renal replacement therapy (RRT) and progression to AKIN stage 3 (23.5% vs 12.6%) was significantly more common in ACLF (p<0.0001). Presence of HRS (28.7% vs 29.2%) and response to terlipressin (44.1% vs 44.3%) was not significantly different in both the groups, however HRS in ACLF was characterized by an increased mortality (67.9% vs 45.9%; p=0.001) and progression to acute tubular necrosis (ATN) with higher need of RRT (53.8%vs 20.4%; p<0.0001). Presence of HRS (p<0.0001, HR 11.3, 95%CI 8.6-15.05) was associated with highest risk of mortality on multivariate analysis. Conclusion: The prevalence, spectrum, natural history and mortality of AKI in ACLF is distinctly different from patients with CLD. Patients with ACLF and HRS have the highest risk of mortality.


The following people have nothing to disclose: Rakhi Maiwall, Suman Kumar, Chitranshu Vashishtha, Manoj Kumar, Hitendra K. Garg, Sumanlata Nayak, Sunil Taneja, Bhaskar Thakur, Shiv K. Sarin


Diagnostic test accuracy of vWF for hepatopulmonary syndrome in patients with liver cirrhosis

Thomas Horvotits, Andreos Drolz, Arnulf Ferlitsch, Christian Müller,Peter Schenk, Valentin Fuhrmonn

Internal Medicine 3, Gostroenterology and Hepatology, Medical University of Vienna, Vienna, Austria

Background: Hepatopulmonary syndrome (HPS) occurs in 20-30% of patients with liver cirrhosis and is associated with a > 2fold increased mortality. Pulmonary angiogenesis and endothelial dysfunction seem to play a central role in its pathogenesis. von Willebrand factor antigen (vWF-Ag), a marker of endothelial dysfunction, is significantly elevated in patients with liver cirrhosis and portal hypertension. vWF levels are associated with increased pulmonary angiogenesis in a rat model of HPS. Single nucleotide polymorphisms (SNPs) in the vWF-gene are associated with HPS. Aim of the present study was to evaluate the relevance of vWF-Ag as a diagnostic marker for HPS in patients with cirrhosis. For this purpose we considered assessment of vWF-Ag as index test and HPS screening as reference standard. Methods: 145 patients (107 male, 38 female; mean age: 56 years) with liver cirrhosis were included in this prospective study. vWF-Ag was assessed by ELISA. All patients were screened for presence of clinically significant HPS according to the established criteria (presence of cirrhosis, AaDO2 > 15mmHg & PaO2 < 80mmHg, intrapulmonary vasodilatation in contrast enhanced echocardiography). (1)Results: Criteria of HPS were fulfilled in 31 patients. Liver cirrhosis was caused mainly by alcoholic liver disease (58%), chronic hepatitis C (26%) and others (16%). vWF-Ag level was significantly higher in patients with HPS compared to patients without HPS (423% (IQR, 387% 519%) vs. 315% (IQR, 248%-417); P < 0, 001). In HPS positive subjects vWF-Ag correlated significantly with gas exchange abnormalities (PaO2 (r = 0, 404, P < 0, 05), AaDO2 (r = 0, 426, P < 0, 05). Univariate analysis showed a significant association between vWF-Ag and presence of HPS (OR per 1% increase of vWF-Ag: 1, 016, 95% Cl: 1, 009-1, 023, P < 0, 001). vWF-Ag remained significantly associated with HPS after correction for sex, age, MELD score and hepatic venous pressure gradient in multivariate analysis (OR per 1% increase of vWF-Ag: 1, 019, 95% Cl: 1, 004-1, 035, P < 0, 05). The area under the ROC curve of vWF-Ag for detection of HPS was 0, 838.The best cut off with maximal sensitivity was 328% (sensitivity of 100% and specificity of 53.5%; positive predictive value: 36.9%; negative predictive value: 100%). Positive likelihood ratio was 2, 15 and negative likelihood ratio was 0, 00.Conclusion: vWF-Ag is a significant predictor for presence of HPS, independently of severity of cirrhosis. Therefore a cut-off level of vWF-Ag > 328% may become a useful marker to identify HPS in patients with cirrhosis. 1.Rodriguez-Roisin R et al. Eur Respir J 2004


Christian Müller - Speaking and Teaching: Bayer, Bayer, Bayer, Bayer

The following people have nothing to disclose: Thomas Horvatits, Andreas Drolz, Arnulf Ferlitsch, Peter Schenk, Valentin Fuhrmann


Stratification based on acute on chronic liver failure (ACLF) has greater prognostic accuracy than stratification based on creatinine, Acute Kidney Injury (AKI), Encephalopathy or Child-Pugh Score. Prognostic relevance of 48 hour post-enrolment ACLF Stratification

Paolo Angeli1, Pere Gines2, Salvatore Piano1, Elisobet Garcίa6, Filippo Morando1, Ezequiel Rodriguez2, Xavier Ariza2, Elisabetta Gola1, Elsa Solá2, Monica Guevara2, Richard Moreau3, Rajiv Jalan4, Juan Cordoba5, Marco Pavesi6, Francois Durand3, Thierry Gustot7, Faouzi Saliba8, Marco Domenicali9, Alexander L. Gerbes10, Julia Wendon11, Carlo Alessandria12, Wim Laleman13, Stefan Zeuzem14, Jonel Trebicka15, Mauro Bernardi9, Vicente Arroyo2

1Unit of Hepatic Emergencies and Liver Transplantatsion, University of Padova, Padova, Italy; 2Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain; 3Service d΄hepatologie, Hôpital Beaujon, Clichy, France; 4lnstitute of hepatology, University College London, London, United Kingdom; 5Liver Unit, Hospital Vall d΄hebron, Barcelona, Spain; 6Data Management Center, CLIF Consortium Hospital Clinic, Barcelona, Spain; 7Department of Gastroenterology and Hepato-Pancreatology, Hospital ERasme ULB, Brussels, Belgium; 8Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France; 9Semeiotica Medica, Policlinico S. Orsola-Malpighi,, Bologna, Italy; 10Liver Centre of Munich, Klinikum der LMU Munchen-Grosshader, Munich, Germany; 11lnstitute of Liver Studies and the Cellular Biology of Inflammation, Kings College Hospital, London, United Kingdom; 12Division of Gastroenterology and Hepatology, San Giovanni Battista Hospital,, Turin, Italy; 13Department of Liver and Biliopancreatic Diseases, University Hospital Gasthuisberg, Leuven, Belgium; 14Department of Medicine I,, JW Goethe University Hospital,, Frankfurt, Germany; 15Department of Internal Medicine I,, University Hospital of Bonn, Bonn, Germany

Background and Aim. Stratification of patients with cirrhosis is a common practice in clinical hepatology. This study compares the prognostic accuracy (28-day and 90-day transplant free mortality) of the ACLF stratification (No ACLF, ACLF grades 1,2 and 3) based on the function of six organs/systems (liver, kidney, brain, coagulation, circulation, lungs) to that based on serum creatinine (<1.2, 1.2-1.4, 1.5-1.9, ≥2 mg/dl), AKIN (No AKI, AKI 1, 2 and 3), hepatic encephalopathy (HE) grade (No HE, HE 1, 2, 3 and 4) and Child-Pugh (A, B, Cし). Additionally, progression or regression of ACLF within 48 h after enrolment and comparison of accuracy of ACLF stratification at enrolment and 48 h after enrolment were also assessed. Patients. The study was performed in 1343 patients with cirrhosis and acute decompensation included in the EASL-CLIF Consortium CANONIC prospective observational study. Results. ACLF stratification at enrolment (1206 patients) was significantly more accurate in predicting 28-day (AUC: 0.78; 0.73-0.82) and 90-day (not shown) mortality than serum creatinine (0.70; 0.66-0.75; p=0.002), HE (0.67; 0.62-0.72; p<0.0001)and Child-Pugh score (0.69; 0.65-0.72; p=0.0002) stratification. Also in the 581 patients with sequential assessment of organ function, ACLF stratification at enrolment was significantly more accurate in predicting prognosis (0.74; 0.69-0.80) than AKI stratification (0.67; 0.62-0.72; p=0.02) assessed on the basis of changes in serum creatinine from enrolment to 48 h after enrolment. Sequential assessment of organ function between enrolment and 48 h after enrolment showed that ACLF stratification remained steady (no change) in 68.3% of patients, improved in 17.2% and worsened in 14.5%. The 28-day mortality correlated with the direction of change in ACLF stratification and the final degree of ACLF (No ACLF at enrolment-steady course 4.7%, AcLF at enrolmentregression to no ACLF 7.7%, improvement of ACLF to grades 1 or 2 30%, progression from no ACLF to ACLF 35.1%, ACLFsteady course 38.4%, progression of ACLF to grades 2 or 3 59.4%). ACLF stratification 48 h after enrolment was significantly more accurate in predicting 28-day (0.82; 0.78-0.87) and 90-day (not shown) mortality than ACLF stratification at enrolment (0.73; 0.68-0.79; p=0.0004). Conclusions. ACLF stratification predicts short-term mortality more accurately than serum creatinine, AKIN, HE or Child-Pugh stratification. ACLF stratification improves or worsens within the first 48 h after enrolment in one-third of patients. The predictive accuracy of ACLF stratification, therefore, improves if assessed 48 h after enrolment.


Pere Gines - Advisory Committees or Review Panels: Ferring; Grant/Research Support: Sequana Medical, Grifols

Rajiv Jalan - Consulting: Ocera Therapeutics, Conatus

Juan Cordoba - Advisory Committees or Review Panels: Ocera

Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis; Speaking and Teaching: Gilead

Faouzi Saliba - Advisory Committees or Review Panels: Novartis, Roche, Genzyme; Grant/Research Support: Astellas; Speaking and Teaching: Schering Plough, Gambro, MSD

Julia Wendon - Consulting: Pulsion, Excalenz

Stefan Zeuzem - Consulting: Abbvie, Achillion Pharmaceuticals, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals, Presidio, Santaris, Inc

Mauro Bernardi - Consulting: CLS Behring GhmB; Speaking and Teaching: CLS Behring GhmB, PPTA Europe

Vicente Arroyo - Speaking and Teaching: GRIFOLS

The following people have nothing to disclose: Paolo Angeli, Salvatore Piano, Elisabet Garcίa, Filippo Morando, Ezequiel Rodriguez, Xavier Ariza, Elisabetta Gola, Elsa Solá, Monica Guevara, Richard Moreau, Marco Pavesi, Thierry Gustot, Marco Domenicali, Alexander L. Gerbes, Carlo Alessandria, Wim Laleman, Jonel Trebicka


Predicting Presence of Clinically Significant Hepatic Involvement in Hereditary Hemorrhagic Telangiectasia using a Simple Clinical Scoring Index

Siddharth Singh1, Karen L. Swanson2, Matthew Hathcock3, Walter K. Kremers3, John Pallanch4, Michael J. Krowka2, Patrick S. Kamath1

1Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN; 2Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN; 3Biostatistics, Mayo Clinic, Rochester, MN; 4Otolaryngology, Mayo Clinic, Rochester, MN

Background: Symptomatic liver disease in hereditary hemorrhagic telangiectasia (HHT) is rare but may be fatal without liver transplantation. Aims: To identify risk factors predictive of clinically significant liver disease. Methods: In this prospective cohort study, we included consecutive patients referred to our HHT center from 2001 with definite HHT. Patients underwent systematic protocol screening, including contrast-enhanced CT. From a multivariable logistic regression model, we developed a simple clinical scoring index that may predict presence of clinically significant liver disease [symptomatic liver disease (cardiac failure, portal hypertension or biliary disease) or at-risk liver involvement with abnormal liver examination (liver bruit, thrill, palpable hepatomegaly) or biochemistry or elevated cardiac index]. Results: Three hundred seventeen patients with definite HHT were included; 171 patients (54.5%; age 50.7±14.7 y, 101 females) had hepatic involvement on imaging. Twenty nine patients had symptomatic liver disease (22 with high-output heart failure, 6 with portal hypertension and 3 with symptomatic biliary disease) and 45 patients had at-risk liver disease. Ninety seven patients (56.7%) had hepatic involve-ment without symptomatic or at-risk liver disease. Using multivariable logistic regression analysis, four clinical variables (age, gender, hemoglobin and alkaline phosphatase) were modeled to develop a simple clinical scoring index (c-statistic to distinguish clinically significant liver involvement and no or incidental liver lesions=0.83). Table shows the probability of clinically significant liver disease based on risk score. Score <3 indicates low risk (<8%), 4-6 moderate (20-60%) and >7, high risk (>60%). Conclusion: About 9% of patients with HHT develop symptomatic liver disease. A simple scoring system using age, gender, hemoglobin and alkaline phosphatase can stratify patients into low, moderate and high risk for clinically significant liver disease.

Estimated probability of clinically significant liver disease in patients with HHT based on Simple Clinical Scoring Index.

Cumulative Score using Simple Clinical Scoring IndexEstimated Probability of Clinically Significant Hepatic Involvement (%)


The following people have nothing to disclose: Siddharth Singh, Karen L. Swanson, Matthew Hathcock, Walter K. Kremers, John Pallanch, Michael J. Krowka, Patrick S. Kamath


The Cirrhosis Dysbiosis Ratio Provides Insight into Gut Microbiome Changes Across the Spectrum of Cirrhosis: A Prospective Study of 250 Patients

Jasmohan S. Bajaj1, Phillip Hylemon2, Douglas M. Heuman1, Arun J. Sonyol1, Patrick M. Gillevet3

1Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical center, Richmond, VA; 2Microbiology, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA; 3Microbiome Analysis Center, George Mason University, Manassas, VA

Gut milieu alterations are associated with cirrhosis complications such as hepatic encephalopathy(HE)and infections. An unfavorable gut microbiome(dysbiosis) could modulate cirrhosis progression. Aim: Evaluate gut microbiota changes across the spectrum of cirrhosis. Methods: Cirrhotics and age-matched controls underwent a cross-sectional stool analysis using multitagged pyrosequencing. Microbiome abundance and cirrhosis dysbiosis ratio (CDR); ratio of the beneficial autochthonous (Lachnospiraceae+Ruminococaceae+Veillonellaceae+Clostridiales Incertae Sedis XIV) and potentially pathogenic taxa abundance (Enterobacteriaceae+Bacteroidaceae) was compared between groups. Results: 250 cirrhotics [(206 outpatients (no HE: 139, HE: 67), infected inpatients: 44] &25 controls were included. Etiology was alcohol 20%, NASH 14%, rest HCV. MELD was highest in inpatients compared to HE & no HE pts (19 vs 14 vs 10, p<0.001), was negatively related to CDR & autochthonous taxa (all p<0.0001) and positively with pathogenic ones; (Staphylococcae, Enterococcaeae &Enterobacteriaceae, p<0.001). With worsening cirrhosis, there was further dysbiosis compared to controls due to autochthonous taxa reduction &pathogenic taxa overgrowth(Table). Dysbiosis (CDR 0.74 vs 0.15, p<0.001) was seen in inpatient vs outpatients. In outpatients HE pts had a significantly lower CDR compared to non-HE (p=0.04). Etiology analysis: Despite similar MELD (12 vs 13) alcoholics had a lower CDR (1.8 vs 3.9) due to lower authochthonous taxa (all p<0.001)compared to non-alcoholics. However NASH cirrhotics had similar CDR(3.8 vs 3.0) than the rest but higher Bacteroidaceae (43 vs 19%, p<0.001), PorphyromcnadaceaeM vs 1%, p=0.003), &lower Veillonellaceae (2 vs 0%, p<0.001). Conclusions: The Cirrhosis Dysbiosis Ratio quantifies the unfavorable gut microbiome that is ssociated with worsening disease severity in this large cirrhotic population. This dysbiosis could be play a role in pathogenesis and progression of cirrhosis.

Significantly Different Microbiota Abundances

Median % taxa abundance (all p<0.001)ControlsCirrhotic no-HE outpatients(n= 139)Cirrhotic HE outpatients(n=67)Cirrhotic Infected Inpatients (n=44)
Bacteroidaceae 19.727.022.49.6
Incertae Sedis XIV5.
Cirrhosis Dysbiosis Ratio2.050.890.660.32


Jasmohan S. Bajaj - Advisory Committees or Review Panels: Salix, Merz, otsuka, ocera, grifols, american college of gastroenterology; Grant/Research Support: salix, otsuka, grifols

Douglas M. Heuman - Consulting: Bayer, Grifols, Genzyme; Grant/Research Support: Exilixis, Novartis, Bayer, Bristol Myers Squibb, Scynexis, Ocera, Mannkind, Salix, Globeimmune, Roche, SciClone, Wyeth, Otsuka, Ikaria, UCB, Celgene, Centocor, Millenium, Osiris; Speaking and Teaching: Otsuka, Astellas

Arun J. Sanyal - Advisory Committees or Review Panels: Gore, Gilead, Abbott, Ikaria; Consulting: Salix, Immuron, Exhalenz, Bayer-Onyx, Genentech, Norgine, GalMed, Novartis, Echosens, Takeda; Grant/Research Support: Salix, Genentech, Genfit, Intercept, Ikaria, Takeda, Gilead; Independent Contractor: UpToDate

Patrick M. Gillevet - Management Position: BioSpherex LLC

The following people have nothing to disclose: Phillip Hylemon