Transjugular intrahepatic portosystemic shunts

Transcription

1 Pre-Transjugular Intrahepatic Portosystemic Shunts (TIPS) Prediction of Post-TIPS Overt Hepatic Encephalopathy: The Critical Flicker Frequency Is More Accurate Than Psychometric Tests Pierre Berlioux, 1 Marie Angèle Robic, 1 Helène Poirson, 1 Sophie Metivier, 1 Philippe Otal, 2 Carine Barret, 1 Frederic Lopez, 3 Jean Marie Peron, 1 Jean Pierre Vinel, 1 and Christophe Bureau 1 Transjugular intrahepatic portosystemic shunts (TIPS) is a second-line treatment because of an increased incidence of overt hepatic encephalopathy (OHE). A better selection of patients to decrease this risk is needed and one promising approach could be the detection of minimal hepatic encephalopathy (MHE). The aim of the present prospective study was to determine whether pre-tips minimal hepatic encephalopathy was predictive of post-tips OHE and to compare Psychometric Hepatic Encephalopathy Sum Score (PHES) and the Critical Flicker Frequency (CFF) in this setting. From May 2008 to January 2011, 54 consecutive patients treated with TIPS were included. PHES and CFF were performed 1 to 7 days before and after TIPS at months 1, 3, 6, 9, and 12 or until liver transplantation or death. Before TIPS, MHE was detected by PHES and CFF in 33% and 39% of patients, respectively. After the TIPS procedure, 19 patients (35%) experienced a total of 64 episodes of OHE. OHE developed significantly more often in patients for whom an indication for TIPS had been refractory ascites, with a history of OHE or of renal failure, lower hemoglobin level, or MHE as diagnosed by CFF. Post- TIPS OHE was more accurately predicted by CFF than by PHES. Absence of MHE at CFF had a good negative predictive value (91%) for the risk of post-tips recurrent OHE, defined as the occurrence of three or more episodes of OHE or of one episode which lasted more than 15 days. The absence of pre-tips history of OHE and a CFF value equal to or greater than 39 Hz had a 100% negative predictive value for post-tips recurrent OHE. Conclusion: Aiming to decrease the rate of post-tips HE, the use of CFF could help selecting patients for TIPS. (HEPATOLOGY 2014;59: ) Transjugular intrahepatic portosystemic shunts (TIPS) have been part of the armamentarium against the complications of portal hypertension for 20 years. As a whole, TIPS proved more effective than alternative treatments in controlling or preventing variceal bleeding and refractory ascites, although meta-analyses failed to show any improvement in survival and evidenced an increased incidence of hepatic encephalopathy (HE). 1-3 Consequently, in most situations TIPS is considered a second-line treatment. 4,5 Three risk factors for post-tips HE have been identified by a recent meta-analysis pooling more than 3,000 patients: age over 65 years, history of previous episodes of HE, and Child-Pugh score equal to or greater than A better selection of the patients based on those criteria should lessen the risk of post- TIPS HE. However, the incidence of post-tips overt HE (OHE) in patients fulfilling these criteria remains close to 30%, so that we clearly need new parameters. One of them could be minimal HE (MHE) which is Abbreviations: CFF, Critical Flicker Frequency; HE, hepatic encephalopathy; MHE, minimal hepatic encephalopathy; OHE, overt hepatic encephalopathy; PHES, Psychometric Hepatic Encephalopathy Sum Score; RBANS, Repeatable Battery for Assessment of Neurological Status; TIPS, transjugular intrahepatic portosystemic shunts From the 1 Service d hepato-gastro-enterologie CHU Toulouse Hopital Purpan et Universite Paul Sabatier, Toulouse, France; 2 Service de radiologie Hopital Rangueil CHU Toulouse et Universite Paul Sabatier, Toulouse, France; 3 Plateforme de Proteomique I2MC Inserm Rangueil Toulouse, France. Received March 15, 2013; accepted August 7, Supported in part by a grant from the Delegation Regionale a la Recherche Clinique des H^opitaux de Toulouse. 622

2 HEPATOLOGY, Vol. 59, No. 2, 2014 BERLIOUX ET AL. 623 considered the first stage in the clinical spectrum of HE 7 and has been associated with an increased risk of OHE MHE is defined as cognitive alterations such as attentional deficit, psychomotor slowing, and troubles in executive functions, while clinical examination remains normal. 11,12 Diagnosis relies on a battery of psychometric tests such as the Psychometric Hepatic Encephalopathy Sum Score (PHES), 13 or Repeatable Battery for Assessment of Neurological Status (RBANS). 14 However, the results of those tests can be influenced by age, educational level, and training of the patients by repeating the tests. Moreover, these tests need normative data, which are not available in most countries and their practice is time-consuming, requiring up to 30 minutes for completion. The Critical Flicker Frequency (CFF) is a simple visual test which has also been validated for diagnosing MHE Over psychometric tests, it has the advantages of being independent of educational level, age, or training, and is fast to perform. CFF could therefore fulfill the criteria required to increase the likelihood of testing for MHE. 18 The present prospective study aimed to determine whether pre-tips MHE was predictive of post-tips HE and to compare PHES and CFF in this specific setting. Patients and Methods All consecutive patients with cirrhosis admitted to our center from may 2008 to January 2011 who were treated with TIPS for a complication of portal hypertension were included in the present study, providing they had none of the following exclusion criteria: TIPS in emergency conditions for uncontrolled bleeding 5 ; presence of OHE, grade II or more, according to the West-Haven criteria 19 at admission; history of recurrent HE, as defined by the Vienna Consensus Conference 12 with more than one episode within the previous year; an opthalmologic disorder making it impossible to perform CFF; or uncooperativeness or illiteracy. During the study period 54 consecutive patients (Supporting Fig. 1) whose main characteristics are listed in Table 1 fulfilled the above criteria and were Table 1. Main Characteristics of the Patients Patients (n 5 54) Gender: women 13 (24%) Age (years) 58 (6 11) Educational level (years) 9 (6 3) TIPS indication Bleeding 19 (35%) Ascites 33 (61%) Others 2 (4%) Cirrhosis etiology Alcohol 45 (83 %) Virus B or C 4 (7 %) Other 5 (10 %) History OHE grade II 19 (35 %) Ascites 41 (76 %) Variceal bleeding 25 (46%) HCC 3 (6 %) Treatment Diuretics 31 (57 %) B-blockers 28 (52 %) Bilirubin (lmol/l) 32 (6 23) Prothrombin ratio (%) 61 (6 14) Albumin (g/l) 32 (6 5) Creatinin (lmol/l) 94 (6 48) Urea (mmol/l) 7 (6 6) Urinary sodium (mmol/l) 14 (6 17) Child-Pugh: A/B/C 11/35/8 Score 7.9 (6 1.5) MELD score 12.8 (6 3) PPG pre-tips (mmhg) 16 (6 5) PPG post-tips (mmhg) 5 (6 2) Mean follow-up (days) 266 (6 136) Median follow-up (days) 365 [2-392] Mean CFF (Hz) 40.1 (6 4.9) Mean PHES (6 3.9) Data are presented as means 6 SD or numbers (and percentages). OHE 5 overt hepatic encephalopathy; PPG 5 portocaval pressure gradient; HCC 5 hepatocellular carcinoma. included. Medications including psychoactive drugs were discontinued, but in four patients they were considered absolutely needed (anticonvulsants in two, antidepressant in one, and neuroleptic in one). None of these four patients had experienced OHE before TIPS. Written informed consent was obtained from each patient and the study was approved by the local Ethics Committee. Psychometric Testing. The five PHES tests (Digit Symbol Test [DSB], Number Connection Test [NCT] A and B, Serial Dot Test [SDT], and Line Tracing Address reprint requests to: Pr. Christophe Bureau, Service d hepato-gastro-enterologie CHU Toulouse Hopital Purpan et Universite Paul Sabatier, Toulouse, Place du Dr Baylac Toulouse Cedex, France. Bureau.c@chu-toulouse.fr; fax: Copyright VC 2013 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Nothing to report. Additional Supporting Information may be found in the online version of this article.

3 624 BERLIOUX ET AL. HEPATOLOGY, February 2014 Test [LTT]) were performed 1 to 7 days before TIPS by two of us (H.P. or P.B.) after specific training. Results were expressed after correction for age and educational level as presented in the freely available Spanish normality tables ( MHE was diagnosed whenever PHES was equal to or below 24. CFF. CFF was performed the same day as PHES in a quiet, semidarkened room by the same examiner. The mean of 10 measures was registered after a few training procedures to ensure patient understanding. The diagnosis of MHE was considered whenever CFF was below 39 Hz. 15 Blood Tests. Peripheral blood was collected on the same day as PHES and CFF and analyzed for routine liver function tests and hematologic parameters by conventional methods under good laboratory practice conditions. Follow-up. After the TIPS procedure, performed as described, 20 patients were followed at months 1, 3, 6, 9, and 12 at outpatient clinics, or until liver transplantation or death. They were not given any prophylactic treatment for OHE. They were evaluated for MHE, symptoms of OHE, their general condition, complications of cirrhosis, and liver function as assessed by usual clinical examination and biochemical tests. Definitions. The following definitions were used: MHE PHES below or equal to 24 and/or CFF below 39 Hz, in the absence of clinical symptoms of OHE 7 ; OHE was diagnosed according to the West-Haven criteria 19 ; recurrent HE (RHE): occurrence of three or more episodes of OHE or one episode of OHE which lasted more than 15 days during follow-up; refractory or persistent HE: persistence of symptoms of HE despite optimal treatment with lactulose and/or nonabsorbable antibiotics such as rifaximin; refractory ascites was defined according to the International Ascites Club guidelines 4 Statistical Methods. Statistical analysis was performed using the SPSS 19 statistical software package (Chicago, IL). Results were expressed as mean 6 SD, or percentage as appropriate. Quantitative variables were analyzed using Student t test and Pearson s or Spearman s correlation coefficient as appropriate. A chi-square test was used for quantitative variables. Multivariate analysis used the Cox regression model. Sensitivity and specificity were assessed by receiver operating characteristic (ROC) curves analysis. Results The main characteristics of the 54 patients are listed in Table 1. PHES could not be properly assessed in Table 2. Number of Episodes of Post-TIPS OHE Per Patient Patients (n) Number Episodes Post-TIPS OHE More than 3 Total two patients because of their misunderstanding of the tests. Analyses concerning PHES were therefore made in 52 patients. CFF was successfully performed in all the patients. Median follow-up was 365 days (range 2-392). Among the 19 patients (35%) who developed OHE and the 10 patients (18%) with RHE post-tips, a total of 64 episodes of HE were registered (Table 2). A possible precipitating event was disclosed in 24 cases: infection in 10 (urinary tract in five, pulmonary in two, septicemia in three), medication in nine (benzodiazepines, neuroleptics, morphin), hyponatremia below 125 meq/l in one, renal failure in two, general anesthesia in one, digestive tract occlusion in one, and posttrauma cerebral hematoma in one. Eleven (20%) patients died during follow-up. The main post-tips clinical events and causes of death are listed in Table 3. Before TIPS, MHE was detected by PHES in 18 out of 52 patients (33%), and by CFF in 21 out of 54 patients (39%). There were no significant correlations between PHES and CFF values (r , P ). When analyzing the components of PHES, CFF was correlated only with LTT (r ; P ) (Supporting Table 1). Using univariate analysis, OHE developed significantly more often in patients for whom an indication for TIPS had been refractory ascites (89% versus 46%), with a history of OHE (53% versus 26%) or of renal failure (58% versus 23%), hepatocellular carcinoma (58% versus 29%), lower hemoglobin level (9.9 g/dl versus 11.2 g/dl) or MHE as diagnosed by CFF (58% versus 29%) (Table 4). Only refractory ascites (P < 0.001) and lower hemoglobin level (P < 0.005) Table 3. Main Clinical Events After TIPS Patients n 5 54 Hepatic encephalopathy 19 (35%) Recurrent hepatic encephalopathy 10 (18%) Refractory and persistent HE 2 (4%) Ascites 6 (11%) Variceal bleeding 1 (2%) Heart failure 9 (17%) Renal failure 8 (15%) HCC 1 (2%) Death 11 (20%)

4 HEPATOLOGY, Vol. 59, No. 2, 2014 BERLIOUX ET AL. 625 Table 4. Comparison Between Patients With Post-TIPS OHE and Free of Post-TIPS OHE No OHE Post-TIPS n 5 35 OHE Post-TIPS n 5 19 P Gender: women 7 (20%) 6 (32%) 0.5 Age (years) 56.5 (6 12) 60.9 (6 10) 0.2 Etiology: alcohol 27 (77%) 18 (95%) 0.3 TIPS indication: ascites 16 (46%) 17 (89%) History OHE 9 (26%) 10 (53%) 0.04 Variceal bleeding 17 (48%) 8 (42%) 0.7 Ascites 24 (68%) 17 (89%) 0.1 Renal insufficiency 8 (23%) 11 (58%) 0.02 HCC 0 3 (16%) 0.04 Ascites 17 (48%) 16 (84%) 0.02 Esophageal varices 27 (77 %) 15 (79%) 1 Prothrombin ratio (%) 61.3 (6 16) 61.4 (6 11) 0.9 Albumin (g/l) 32.1 (6 5) 31.6 (6 4.5) 0.7 Bilirubin (lmol/l) 31.2 (6 21.8) 33.6 (6 24.7) 0.7 Serum sodium (mmol/l) (6 6.5) (6 4) 0.6 Serum creatinin (lmol/l) 88.4 (6 40) 105 (6 59) 0.2 Urea (mmol/l) 6.2 (6 3.6) 10 (6 8.5) 0.09 Hemoglobin (g/dl) 11.2 (6 2.1) 9.9 (6 1.5) 0.01 Platelets (10 9 /mm 3 ) ( ) ( ) 0.8 CRP (mg/l) 19.3 (6 27) 22.7 (6 21) 0.6 Ammonia(lmol/l) 75.6 (6 43) 94.8 (6 58) 0.3 MELD score 12.6 (6 3.7) 13.2 (6 3) 0.5 Child Pugh score 7.8 (6 1.6) 8.3 (6 1.1) 0.2 PPG post-tips 5 (6 1.6) 5 (6 1.8) 0.9 DST 33.4 (6 15.4) 27.9 (6 12.9) 0.2 NCT-A 59.6 (6 33.7) 94.4 (6 71) 0.06 NCT-B 159 (6 91) 237 (6 164) 0.07 SDT 70 (6 32) 86 (6 41) 0.1 LTT 122 (6 55.6) 151 (6 83.6) 0.1 PHES 22.1 (6 3.6) 23.9 (6 4.4) 0.1 CFF 40.7 (6 4.6) 38.9 (6 5.2) 0.1 MHE PHES 10 (29%) 8 (42%) 0.4 MHE CFF 10 (29%) 11 (58%) 0.03 Data are presented as means 6 SD or numbers (and percentages). OHE 5 overt hepatic encephalopathy; HCC 5 hepatocellular carcinoma; PPG 5 portocaval pressure gradient. were identified as independent predictors of OHE by Cox analysis. RHE was significantly more frequent in patients with higher age, refractory ascites as TIPS indication, history of renal failure, lower hemoglobin level, or MHE as diagnosed by CFF (Table 5). Using the Cox model, refractory ascites (P < 0.01) and lower hemoglobin level (P < 0.02) were found to be independent predictive factors for RHE. MHE as diagnosed by PHES was not predictive of either OHE or RHE post-tips (Figs. (1 and 2)). On the contrary, MHE as diagnosed by CFF was predictive of post-tips OHE (Figs. (1 and 2)). Area under the ROC curve analysis of CFF for the prediction of post-tips OHE was 0.67 ( ; P < 0.05) with an optimal threshold of 39 Hz. Accordingly, when the CFF value was greater than or equal to 39 Hz the probability of remaining free of OHE was 73% versus 42% when it was lower. The figures were 88% versus 64%, respectively, when considering RHE. Patients with no history of OHE and a CFF value greater than or equal to 39 Hz had a probability of remaining free of OHE of 86% versus 41% for those who did not and free of RHE of 100% versus 64%, respectively (Fig. 3). Negative predictive values of CFF were 76% for OHE and 91% for RHE (Supporting Table 2). Factors found associated with death were higher age or Child-Pugh score, lower hemoglobin level, and refractory ascites as TIPS indication. Pre-TIPS MHE disclosed by either PHES or CFF was not associated with survival. Discussion The main findings of this prospective study evaluating the predictive value of pre-tips minimal hepatic encephalopathy for post-tips overt hepatic encephalopathy, using and comparing PHES and CFF were: (1) through the diagnosis of MHE, CFF was more accurately predictive of post-tips OHE than PHES;

5 626 BERLIOUX ET AL. HEPATOLOGY, February 2014 Table 5. Comparison Between Patients With Post-TIPS RHE and No Post-TIPS RHE Univariate Analysis No Recurrent OHE n 5 44 Recurrent OHE n 5 10 P Gender: women 9 (20%) 4 (40%) 0.2 Age (years) 57 (6 12) 63 (6 5.6) 0.02 Etiology: alcohol 35 (79%) 10 (100%) 0.18 TIPS indication: ascites 24 (54%) 9 (90%) 0.05 History OHE 13 (29.5%) 6 (60%) 0.07 Variceal bleeding 2 (4.5%) 3 (30%) 0.3 Ascites 32 (73%) 9 (90%) 0.2 Renal insufficiency 12 (28%) 7 (70%) 0.02 HCC 1 (2%) 2 (20%) 0.08 Ascites 25 (57%) 8 (80%) 0.2 Esophageal varices 35 (79%) 7 (70%) 0.9 Prothrombin ratio (%) 61.2 (6 15) 62 (6 10) 0.9 Albumin (g/l) 32.1 (6 4.7) 31.2 (6 5.7) 0.6 Bilirubin (lmol/l) 32.6 (6 21) 29.7 (6 27) 0.7 Serum sodium (mmol/l) 133 (6 6) 134 (6 3.5) 0.4 Serum creatinin (lmol/l) 92 (6 49) 103 (6 41) 0.5 Urea (mmol/l)gamma-gt (UI/l) 7.1 (6 5.6) 9.7 (6 7.6) 0.1 Hemoglobin (g/dl) 11.1 (6 2) 9.4 (6 1.2) Platelets (10 9 /mm 3 ) ( ) ( ) 0.5 CRP (mg/l) 19.9 (6 25) 23.3 (6 23) 0.7 Ammonia (lmol/l) 76.3 (6 37) (6 72) 0.2 MELD score 12.9 (6 3.5) 12.6 (6 3) 0.8 Child-Pugh score 7.9 (6 1.6) 8.2 (6 0.8) 0.3 PPG post-tips (mmhg) 4.9 (6 1.6) 5.8 (6 1.7) 0.3 DST 32.9 (6 14.7) 25.8 (6 13.8) 0.2 NCT-A 67 (6 45.6) 91(6 72) 0.2 NCT-B 176 (6 113) 225 (6 169) 0.3 SDT 73 (6 35) 85 (6 38) 0.3 LTT 139 (6 71) 143 (6 46) 0.6 PHES 22.4 (6 3.8) 24.2 (6 4.2) 0.2 CFF 40.6 (6 5) 37.8 (6 4) 0.07 MHE PHES 14 (32%) 4 (40%) 0.5 MHE CFF 14 (32%) 7 (70%) 0.03 Data are presented as means 6 SD or numbers (and percentages). HE 5 hepatic encephalopathy; HCC 5 hepatocellular carcinoma; PPG 5 portocaval pressure gradient. Fig. 1. Prediction of OHE in patients with cirrhosis and TIPS (A) by CFF (log-rank P ) and (B) by PHES (log-rank P 5 0.3).

6 HEPATOLOGY, Vol. 59, No. 2, 2014 BERLIOUX ET AL. 627 Fig. 2. Prediction of RHE in patients with cirrhosis and TIPS (A) by CFF (log-rank P ) and (B) by PHES (log-rank P 5 0.6). (2) absence of MHE at CFF had a good negative predictive value (91%) for the risk of post-tips RHE; (3) the absence of pre-tips history of HE and a CFF value equal to or greater than 39 Hz had a 100% negative predictive value (NPV) for post-tips RHE. According to an American Association for the Study of Liver Diseases (AASLD) survey, a simple and rapid test for MHE diagnosis would increase the likelihood of testing for MHE. 18 CFF might fulfill those criteria, having the advantages over psychometric tests of being fast and simple to perform and to interpret, independent of language, educational level, age, or training. In our patients, the prevalence of pre-tips MHE was 33% and that of post-tips OHE was 35%, which is similar to the figures reported in the literature. 21 Three risk factors have been identified in the literature: age above 65 years, history of HE, and Child- Pugh score over 9. 6 Both age and history of HE were also predictive factors of OHE in our patients, while Child-Pugh and MELD scores were not. This could Fig. 3. Combination of CFF and history of HE in patients with cirrhosis and TIPS to predict (A) OHE (log-rank P ) and (B) RHE (logrank P ).

7 628 BERLIOUX ET AL. HEPATOLOGY, February 2014 be due to our stringent selection of patients eligible for TIPS as assessed by their mean Child-Pugh score of , mean MELD score of before TIPS, resulting in a 80% survival rate, 1 year after the procedure. It is noteworthy that the mean MELD score of patients with refractory ascites in the present study was similar to that observed in previous reports (12.5 in the meta-analysis of Salerno et al. 3 ). The predictive value of psychometric tests for post- TIPS OHE has been assessed, but the results of published studies were discrepant In our patients neither PHES as a whole nor each of its constitutive psychometric tests proved able to predict post-tips HE, contrary to CFF. This could be accounted for by assessing different neurological functions of the tests. In keeping with this hypothesis, it has been shown that PHES was correlated with markers of inflammation such as C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-a), whereas EEG changes correlated with ammonia and indole concentrations. 25 Moreover, PHES and EEG were independent predictors of HE and death. PHES has been shown to be correlated with psychometric and neurophysiological tests evaluating attentional deficits, but not with those assessing psychomotor slowing. 26 In the latter study, CFF was correlated with DST, NCT-B, and LTT, but not with NCTA, SDT, nor other tests of attention. In our study, CFF was correlated with LTT only. Although there is no clear explanation for these discrepancies, one can speculate that post-tips HE could correspond to a more profound alteration of psychomotor activity than of attention capacities. Furthermore, such a result could indicate that to ascertain the diagnosis and/or predictive value of the tests used in HE, each test should be specifically assessed in different clinical conditions. The performance of other automatic tests, such as an inhibitory control test 27 or driving simulator, 28 should be evaluated and compared with CFF but, unfortunately, these latter tests were not available in our center. In keeping with the results of the Biecker et al. study, 29 pre-tips MHE was not predictive of post- TIPS survival in our study, contrary to what has been reported by Kircheis et al. 30 This could be accounted for by, once again, selecting patients with low Child-Pugh or Meld score, and low 1-year mortality. Furthermore, it must be kept in mind that, due to the relatively small sample of patients, the beta-risk in statistical analysis was not low in our study. Criteria used for selecting patients for TIPS might not bethesameaccordingtowhethertheyhaverefractory ascites, where quality of life can be considered the main purpose of any treatment, or variceal bleeding, a lifethreatening situation. Accordingly, the 100% NPV for RHE of the association of absence of history of previous OHE and CFF equal to or greater than 39 Hz could be of clinical interest in patients with refractory ascites for whom RHE could be considered an overwhelming complication regarding the benefits of effective ascites therapy. A lower hemoglobin level was associated with a higher risk post-tips OHE and RHE in our patients. All patients with a hemoglobin level below 9.5 g/dl experienced HE and among them six had RHE (data not shown). This could be accounted for by several hypotheses. Lower hemoglobin level could be secondary to a more severe portal hypertension with chronic occult bleeding but PPG value was not predictive of post-tips OHE and was not correlated with hemoglobin level. This could be related to a more severe underlying liver disease, but it was not correlated with either Child-Pugh or MELD score. Whatever the cause of anemia, its predictive value could be explained by the fact that hemoglobin metabolites, namely, hemin and protoporphyrin IX, mimic benzodiazepines, interact with the benzodiazepines site on the c-aminobutyric acid (GABA) receptor, and enhance inhibitory synaptic transmission. 31 It is to be noted that hemolysis has been found to be a complication of TIPS in up to 10% of the patients. 32 This could influence the high post-tips OHE incidence. Further studies are needed to clarify this issue. Finally, it is noteworthy that 39 Hz was the best cutoff value both for diagnosing MHE and for predicting post- TIPS OHE, in accordance with the results of Kircheis et al. 15 and a recent meta-analysis. 33 Using this threshold to contraindicate TIPS, 21 patients would not have been treated and the incidence of post-tips OHE would have been 27%, and that of RHE 12%. Most important, adding the absence of previous OHE, the figures would have been 14% and 0%, respectively. However, using those criteria 32 patients would have been excluded for TIPS. Other tests are needed in order to decrease the number of patients for whom TIPS should be contraindicated, especially those with refractory ascites. In conclusion, the use of CFF with a threshold of 39 Hz could help selecting patients for TIPS, in order to decrease the rate of post-tips HE, mainly RHE in patients treated for refractory ascites. References 1. Papatheodoridis GV, Goulis J, Leandro G, Patch D, Burroughs AK. Transjugular intrahepatic portosystemic shunt compared with endoscopic treatment for prevention of variceal rebleeding: a meta-analysis. HEPATOLOGY 1999;30:

8 HEPATOLOGY, Vol. 59, No. 2, 2014 BERLIOUX ET AL Albillos A, Banares R, Gonzalez M, Catalina MV, Molinero LM. A meta-analysis of transjugular intrahepatic portosystemic shunt versus paracentesis for refractory ascites. J Hepatol 2005;43: Salerno F, Camma C, Enea M, Rossle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 2007;133: Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, et al. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. HEPATOLOGY 2003;38: de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005;43: Bai M, Qi X, Yang Z, Yin Z, Nie Y, Yuan S, et al. Predictors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in cirrhotic patients: a systematic review. J Gastroenterol Hepatol 2011;26: Bajaj JS, Cordoba J, Mullen KD, Amodio P, Shawcross DL, Butterworth RF, et al. Review article: the design of clinical trials in hepatic encephalopathy an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement. Aliment Pharmacol Ther 2011;33: Hartmann IJ, Groeneweg M, Quero JC, Beijeman SJ, de Man RA, Hop WC, et al. The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol 2000;95: Romero-Gomez M, Boza F, Garcia-Valdecasas MS, Garcia E, Aguilar- Reina J. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 2001;96: Saxena N, Bhatia M, Joshi YK, Garg PK, Dwivedi SN, Tandon RK. Electrophysiological and neuropsychological tests for the diagnosis of subclinical hepatic encephalopathy and prediction of overt encephalopathy. Liver 2002;22: Schomerus H, Hamster W. Neuropsychological aspects of portalsystemic encephalopathy. Metab Brain Dis 1998;13: Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, HEPATOLOGY 2002;35: Weissenborn K, Ennen JC, Schomerus H, Ruckert N, Hecker H. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001;34: Randolph C, Hilsabeck R, Kato A, Kharbanda P, Li YY, Mapelli D, et al. Neuropsychological assessment of hepatic encephalopathy: ISHEN practice guidelines. Liver Int 2009;29: Kircheis G, Wettstein M, Timmermann L, Schnitzler A, Haussinger D. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. HEPATOLOGY 2002;35: Romero-Gomez M, Cordoba J, Jover R, del Olmo JA, Ramirez M, Rey R, de Madaria E, et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. HEPATOLOGY 2007;45: Sharma P, Sharma BC, Puri V, Sarin SK. Critical flicker frequency: diagnostic tool for minimal hepatic encephalopathy. J Hepatol 2007; 47: Bajaj JS, Etemadian A, Hafeezullah M, Saeian K. Testing for minimal hepatic encephalopathy in the United States: an AASLD survey. HEPA- TOLOGY 2007;45: Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy. A controlled, double-blind clinical trial. Am J Dig Dis 1978;23: Bureau C, Garcia-Pagan JC, Otal P, Pomier-Layrargues G, Chabbert V, Cortez C, et al. Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 2004;126: Gines P, Uriz J, Calahorra B, Garcia-Tsao G, Kamath PS, Del Arbol LR, et al. Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis. Gastroenterology 2002;123: Nolte W, Wiltfang J, Schindler C, Munke H, Unterberg K, Zumhasch U, et al. Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: clinical, laboratory, psychometric, and electroencephalographic investigations. HEPATOLOGY 1998;28: Sanyal AJ, Freedman AM, Shiffman ML, Purdum PP 3rd, Luketic VA, Cheatham AK. Portosystemic encephalopathy after transjugular intrahepatic portosystemic shunt: results of a prospective controlled study. HEPATOLOGY 1994;20: Riggio O, Masini A, Efrati C, Nicolao F, Angeloni S, Salvatori FM, et al. Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study. J Hepatol 2005;42: Montagnese S, Biancardi A, Schiff S, Carraro P, Carla V, Mannaioni G, et al. Different biochemical correlates for different neuropsychiatric abnormalities in patients with cirrhosis. HEPATOLOGY 2011;53: Felipo V, Ordono JF, Urios A, El Mlili N, Gimenez-Garzo C, Aguado C, et al. Patients with minimal hepatic encephalopathy show impaired mismatch negativity correlating with reduced performance in attention tests. HEPATOLOGY 2012;55: Bajaj JS, Saeian K, Verber MD, Hischke D, Hoffmann RG, Franco J, et al. Inhibitory control test is a simple method to diagnose minimal hepatic encephalopathy and predict development of overt hepatic encephalopathy. Am J Gastroenterol 2007;102: Bajaj JS, Hafeezullah M, Franco J, Varma RR, Hoffmann RG, Knox JF, et al. Inhibitory control test for the diagnosis of minimal hepatic encephalopathy. Gastroenterology 2008;135: e Biecker E, Hausdorfer I, Grunhage F, Strunk H, Sauerbruch T. Critical flicker frequency as a marker of hepatic encephalopathy in patients before and after transjugular intrahepatic portosystemic shunt. Digestion 2011;83: Kircheis G, Bode JG, Hilger N, Kramer T, Schnitzler A, Haussinger D. Diagnostic and prognostic values of critical flicker frequency determination as new diagnostic tool for objective HE evaluation in patients undergoing TIPS implantation. Eur J Gastroenterol Hepatol 2009;21: Ruscito BJ, Harrison NL. Hemoglobin metabolites mimic benzodiazepines and are possible mediators of hepatic encephalopathy. Blood 2003;102: Sanyal AJ, Freedman AM, Purdum PP, Shiffman ML, Luketic VA. The hematologic consequences of transjugular intrahepatic portosystemic shunts. HEPATOLOGY 1996;23: Torlot FJ, McPhail MJ, Taylor-Robinson SD. Meta-analysis: the diagnostic accuracy of critical flicker frequency in minimal hepatic encephalopathy. Aliment Pharmacol Ther 2013;37: