- Email: [email protected]
Minimal Hepatic Encephalopathy and Critical Flicker Frequency Are Associated With Survival of Patients With Cirrhosis
Gastroenterology 2015;-:1–7
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61 62 63 64 65 66 67 68 Javier Ampuero,1 Macarena Simón,2 Carmina Montoliú,3 Rodrigo Jover,4 Miguel Ángel Serra,5 69 Juan Córdoba,2 and Manuel Romero-Gómez1 70 71 1 Unit for the Clinical Management of Digestive Diseases and CIBERehd, Valme University Hospital, Sevilla, Spain; 2 3 72 Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebrón, Barcelona, Spain; Instituto de Investigación 73 Sanitaria–INCLIVA, Valencia, Spain; 4Gastroenterology Department, Hospital General Universitario, Alicante, Spain; 5 Hepatology Unit, Hospital Clínico Universitario, Valencia, Spain 74 75 BACKGROUND & AIMS: Minimal hepatic encephalopathy outcomes of patients with specific MELD scores. The CFF could 76 (MHE) is associated with falls, traffic accidents, and overt HE. help physicians determine prognoses of patients with cirrhosis. 77 However, the association with survival is controversial. We 78 assessed the effects of MHE on the long-term survival of pa79 tients with cirrhosis. METHODS: We performed a prospective Keywords: PHES; Prognostic Factor; Mortality; Liver Fibrosis. 80 study of 117 consecutive patients with cirrhosis seen at a ter81 tiary hospital in Seville, Spain (estimation cohort), followed by a 82 epatic encephalopathy (HE) is one of the major Q9 Q10 83 validation study of 114 consecutive patients with cirrhosis seen Q11 complications of cirrhosis, affecting one third of at 4 hospitals in Spain from January 2004 through December 84 2007. Patients were examined every 6 months at outpatient cirrhotic patients. It has a relevant socioeconomic impact Q12 85 clinics through December 2013 (follow-up periods of 5 ± 2.8 y because HE reduces quality of life and is associated with a 86 and 4.4 ± 3.9 y for each group, respectively). Cirrhosis was higher mortality rate.1 As a consequence, the appropriate 87 identified by liver biopsy, ultrasound, endoscopic analysis, and scientific bodies (the American Association for the Study of 88 biochemical parameters. Liver dysfunction was determined Liver Diseases and the European Association for the Study 89 based on model for end-stage liver disease (MELD) and Child– of the Liver) released practice guidelines in 2014 for the 2 Pugh scores. All patients were administered the critical flicker management of HE. Furthermore, 30%–50% of cirrhotic Q13 90 91 frequency (CFF) test and psychometric hepatic encephalopathy patients showed minimal hepatic encephalopathy (MHE)3 92 scores were used to detect MHE. Survival curves were when tested by neuropsychological tests such as the Psy93 compared using the log-rank test and multivariable analysis chometric Hepatic Encephalopathy Score (PHES) or neuro94 was performed using Cox proportional hazards models. physiological methods such as critical flicker frequency 95 RESULTS: The distributions of Child–Pugh scores were as fol(CFF), representing the first stage in the HE spectrum.4 MHE 96 lows: 66% class A, 31% class B, and 3% class C in the estiis defined as the presence of cognitive abnormalities in 97 mation cohort, and 50% class A, 32% class B, and 18% class C in the validation cohort. In the estimation cohort, 24 of 35 patients with liver disease, which are not detected with the 98 patients (68.6%) with a CFF score less than 39 Hz survived for standard examinations, but rather is diagnosed only by us99 neuropsychological and neurophysiological 5 years, whereas 50 of 61 patients (82%) with a CFF score of ing sensitive 100 5 39 Hz or higher survived during the follow-up period (log-rank tests. MHE predicts the appearance of overt HE in cirrhotic 101 6 7,8 score, 5.07; P ¼ .024). Psychometric hepatic encephalopathy patients, impairs motor vehicle driving abilities, and in102 9 scores did not correlate with survival. In multivariable analysis, creases the risk of falling over. However, the relationship 103 older age (hazard ratio [HR], 1.07; 95% confidence interval [CI], with mortality has not been widely assessed. Conversely, the 104 1.02–1.12; P ¼ .009), CFF score less than 39 Hz (HR, 4.36; 95% model for end-stage liver disease (MELD) score quantifies 105 CI, 1.67–11.37; P ¼ .003), and MELD score (HR, 1.40; 95% CI, end-stage liver disease and is used widely as a criterion in 106 10 1.21–1.63; P ¼ .0001) were associated independently with liver transplant decision making. The MELD score com107 survival during the follow-up period. In the validation cohort, prises bilirubin level, creatinine level, and the institutional 108 CFF score less than 39 Hz and MELD score also were associated normalized ratio, but does not include clinical variables. Q14 109 with patient survival during the follow-up period. MHE had no Over the past decade, several modifications have been 110 effect on the survival of patients with MELD scores less than 10 proposed to improve and refine the MELD score.11 111 (among patients with CFF scores 39 Hz, 94.5% survived for 5 112 years vs 91.9% of patients with CFF scores <39 Hz; log-rank 113 score, 0.64; P ¼ .423). Fewer patients with MELD scores of 114 10–15 and MHE survived for 5 years (44.4%; 12 of 27) than Abbreviations used in this paper: CI, confidence interval; CFF, critical flicker frequency; DST, digit symbol test; HE, hepatic encephalopathy; HR, 115 those with MELD scores greater than 15 without MHE (61.5%; hazard ratio; MELD, model for end-stage liver disease; MHE, minimal 116 8 of 13) (P < .05). Only 2 of 12 patients (16.7%) with MELD hepatic encephalopathy; NCT, number connection test; PHES, Psycho117 scores of 15 or higher and MHE survived for 5 years (log-rank metric Hepatic Encephalopathy Score. 118 score, 90.56; P ¼ .0001). CONCLUSIONS: MHE is associated © 2015 by the AGA Institute 119 with a reduced 5-year survival rate of patients with cirrhosis. 0016-5085/$36.00 Evaluation of MHE could help predict survival times and 120 http://dx.doi.org/10.1053/j.gastro.2015.07.067
Minimal Hepatic Encephalopathy and Critical Flicker Frequency Are Associated With Survival of Patients With Cirrhosis
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The aims of the present study were to determine prospectively the clinical impact of MHE on long-term overall survival in patients with cirrhosis and, as well, to determine the influence of MHE on the MELD score to rationalize the liver transplantation waiting lists.
Materials and Methods Patient Selection We prospectively recruited 2 independent cohorts: (1) a single-centered estimation cohort (n ¼ 117) of consecutive cirrhotic patients from the Valme University Hospital, and (2) a multicenter validation cohort (n ¼ 114) of consecutive patients with cirrhosis from 4 Spanish hospitals (Figure 1). All patients were recruited between January 2004 and December 2007, and were followed up every 6 months in the outpatient clinics until December 2013. Cirrhosis was defined by liver biopsy, ultrasound, endoscopic analysis, and biochemical parameters. Liver dysfunction was evaluated by MELD and Child–Pugh scores. Exclusion criteria were as follows: age 18 years and younger; diagnosis of hepatocellular carcinoma before enrollment; patients with ongoing treatment for viral cirrhosis; history of recent (<3 mo) alcohol abuse; infection; recent (<6 wk) antibiotic use or gastrointestinal bleeding; and a history of recent (<6 wk) use of benzodiazepines, anti-epileptic, or psychotropic drugs. All patients were assessed with PHES and CFF, both to detect MHE. Of the patients, 5 were found to be almost illiterate and, hence, were unable to perform the PHES, 21 patients were unable to read or count correctly, and had inadequate eyesight (with or without correction spectacles) to be tested accurately with the CFF test. Patients underwent an upper gastrointestinal endoscopy to detect the presence of esophageal varices. All patients provided written informed consent for the collection and storage of peripheral blood mononuclear cells, as well as host DNA testing for research purposes consistent with the current study. All data, including clinical, demographic, and test results, were coded and deposited in the original clinical database. The protocol was approved by the ethics committees of the participating hospitals. The study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice.
Figure 1. Flow of participants in the study.
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Clinical End Points The main outcome of the current study was mortality-free survival. Our first aim was to evaluate the impact of MHE on long-term survival. Our second aim was to incorporate the routine MHE detection, controlling for MELD score, to improve survival prediction. The data from the 5 first years of follow-up evaluation were used to anticipate the requirement for liver transplantation in patients with poor prognosis. Other outcomes such as overt HE, variceal bleeding, ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome were recorded and clinically managed according to current guidelines.12,13
Encephalopathy Management MHE was based on PHES and CFF (Hepatonorm Analyzer; nevoLAB GmbH, Maierhöfen, Germany), which were measured at the same outpatient visit. Both tests were performed by the same expert operator in each center. Patients were classified as having MHE when the PHES score was below -4 points, or the CFF score was below the cut-off value (39 Hz).14,15 The PHES comprises the digit symbol test (DST), the number connection test A (NCT-A), the number connection test B (NCT-B), the serial dotting test, and the line drawing test. The retinal glial cells in patients with HE undergo similar changes to those seen in cerebral glial cells,16 and this observation forms the basis of CFF. The device uses a stepwise decrease in frequency from 60 to 25 Hz. Patients taking rifaximin, branched-chain amino acids, or ammonia decreasing drugs were excluded because these treatments could influence MHE values.
Statistical Analyses Statistical analyses and graphics were performed with SPSS (19.0; SPSS, Inc, Chicago, IL). Continuous variables are presented as means ± SD, whereas discrete outcomes are expressed as percentages. Comparisons between groups were made using the Mann–Whitney U test, the Student t test, or analysis of variance for continuous variables, and the chisquare test or the Fisher exact test (when expected values in any of the cells of a contingency table were less than 5) for categoric data. Survival curves were compared using the Kaplan–Meier method (log-rank test) because time to mortality is crucial in interpreting the results. Variables that showed significance at a P value less than .05 in univariable analysis were entered into backward logistic regression analysis. Collinearity between CFF and PHES with MELD was ruled out. The multivariable models were constructed sequentially with variables entered individually, and a significance level of a P value greater than .05 was used to remove the variables from the model (except age and sex, which were included in all the models as well as albumin and the presence of esophageal varices because these are well-documented predictors of survival in cirrhotic patients). The method used for missing data was complete-case analysis because statistical packages excluded individuals with any missing value. To address the first aim of the study, we analyzed the impact of MHE on longterm survival in the estimation cohort, and subsequently applied in the validation cohort. To address the second aim of the study, we assessed the influence of MHE added to the MELD score in the overall cohort, but excluded patients undergoing liver transplantation as a potential confounding variable. The MELD score was categorized into 3 groups. We established the
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first group as a MELD score of 10 based on the receiver operator characteristic analysis of our data (area under the receiver operator characteristic curve, 0.81; 95% confidence interval [CI], 0.75–0.88; P ¼ .0001) with a sensitivity of 88% and a specificity of 72%. A MELD score of 15 defined the second group according to the worldwide consensus for those patients who needed to be included on the liver transplant waiting list. The third group comprised those patients with a MELD score between 10 and 15.
Results Baseline Characteristics of the Cohorts
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In the estimation cohort, we enrolled 117 cirrhotic patients with different etiologies: alcohol 53% vs no alcohol 47%. Liver function was classified as follows: Child–Pugh A, 65.8%; Child–Pugh B, 30.8%; Child–Pugh C, 3.4%; and MELD scores (10 ± 4). In the estimation cohort, 15 of 117 (12.8%) patients had experienced a previous overt HE event, 30 of 117 (25.6%) had variceal bleeding, 62 of 117 (53%) had ascites, 6 of 117 (5.1%) had spontaneous bacterial peritonitis, and 5 of 117 (4.3%) had hepatorenal syndrome at the time of enrollment. Esophageal varices were present in 88 of 117 (75.2%) patients. CFF was pathologic in 36.5% and PHES was pathologic in 25.9% of patients. These patients were followed up for 5 ± 2.8 years (Table 1). The validation cohort had 114 cirrhotic patients of different etiologies: alcohol 43% vs nonalcohol 57%. Liver function was classified as follows: Child–Pugh A, 50%; Child–Pugh B, 31.6%; Child–Pugh C, 18.4%; and MELD scores (12 ± 5.7). Within this cohort, 19 of 114 (16.7%) had experienced a previous overt HE event at the time of enrollment. Esophageal varices were present in 66 of 96 (68.8%) patients. CFF was pathologic in 47.4%, and PHES was present in 29.8% of patients. These patients were followed up for 4.4 ± 3.9 years.
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MHE and Survival In the estimation cohort, we found that a CFF score less than 39 Hz was related to lower survival rates (24 of 35; 68.6%) than a CFF of 39 Hz or greater (50 of 61; 82%) patients (log-rank, 5.073; P ¼ .024) (Figure 2A). An altered PHES was not related to a poorer prognosis by the end of the follow-up period (PHES < -4: 20 of 29 [69%] vs PHES -4: 67 of 83 [80.7%] patients; log-rank: 2.762; P ¼ .097). Other variables associated with survival were age and MELD score. In multivariable analysis, older age (hazard ratio [HR], 1.07; 95% CI, 1.02–1.12; P ¼ .009), CFF score less than 39 Hz (HR, 4.36; 95% CI, 1.67–11.37; P ¼ .003), and MELD score (HR, 1.40; 95% CI, 1.21–1.63; P ¼ .0001) were independent variables associated with impaired survival (Table 2). In the validation cohort, a CFF score less than 39 Hz was related to a poor prognosis by the end of the followup period (31 of 54; 57.4%) compared with a CFF score of 39 Hz or greater (42 of 60; 70%) patients (log-rank, 4.752; P ¼ .029) (Figure 2B). Age, MELD score, and albumin level also were associated with survival in univariable analysis. In multivariable analysis adjusted for sex, age, and albumin level, a CFF score less than 39 Hz (HR, 2.29; 95% CI, 1.28–4.08; P ¼ .005), and the MELD score (HR, 1.07; 95% CI, 1.03–1.11; P ¼ .0001) were independent variables associated with impaired survival.
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MHE and Cirrhosis Outcomes The CFF score predicted the appearance of overt HE during the follow-up evaluation, results in the estimation cohort were as follows: CFF score less than 39 Hz, 13 of 35 (37.1%) vs CFF score of 39 Hz or higher, 15 of 61 (24.6%) patients (log-rank, 4.896; P ¼ .027); and results in the validation cohort were as follows: CFF score less than 39 Hz, 21 of 54 (38.9%) vs CFF score of 39 Hz or higher, 11 of 60 (18.3%) patients (log-rank, 9.576; P ¼ .002). Overt HE was
Table 1.Baseline Characteristics and Outcomes in the Estimation and Validation Cohorts During Follow-Up Evaluation
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Validation cohort (N ¼ 114)
Sex distribution, males Age ± SD, y MELD score ± SD Child–Pugh score, A/B/C Alcohol-related cirrhosis Esophageal varices Previous HE event Previous variceal bleeding Previous ascites Previous SBP Previous hepatorenal syndrome CFF < 39 Hz PHES < -4 Overt HE Liver transplantation All-cause mortality Liver-related mortality
74.4% (87/117) 57.8 ± 10.8 9.8 ± 4 77/36/4 53% (62/117) 75.2% (88/117) 12.8% (15/117) 25.6% (30/117) 53% (62/117) 5.1% (6/117) 4.3% (5/117) 36.5% (35/96) 25.9% (29/112) 30.8% (36/117) 14.5% (17/117) 21.4% (25/117) 72% (18/25)
71.9% (82/114) 57.3 ± 11.1 12 ± 5.6 57/36/21 43% (49/114) 68.8% (66/96) 16.7% (19/114)
47.4% 29.8% 28.1% 14.9% 36% 65.8%
(54/114) (34/114) (32/114) (17/114) (41/114) (27/41)
NOTE. Previous cirrhosis outcomes were not obtained for the validation cohort because this was not the aim of the study. SBP, spontaneous bacterial peritonitis.
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associated with survival in the estimation (41.7% [15 of 36] vs 12.3% [10 of 81]; P ¼ .0001) as well as the validation cohort (50% [16 of 32] vs 30.5% [25 of 82]; P ¼ .050). However, these test results were not related to variceal bleeding: CFF score less than 39 Hz, 12 of 35 (34.3%) vs CFF score of 39 Hz or higher, 17 of 61 (27.9%) patients (P ¼ .510); ascites: CFF score less than 39 Hz: 14 of 35 (40%) vs CFF score of 39 Hz or higher, 21 of 61 (34.4%) patients (P ¼ .585); spontaneous bacterial peritonitis: CFF score less than 39 Hz, 4 of 35 (11.4%) vs CFF score of 39 Hz or higher, 3 of 61 (4.9%) patients (P ¼ .253); hepatorenal syndrome: CFF score less than 39 Hz, 7 of 35 (20%) vs CFF score of 39 Hz or greater, 7 of 61 (11.5%) patients (P ¼ .255); or hepatocellular carcinoma: CFF score less than 39 Hz, 8 of 35 (22.9%) vs CFF score of 39 Hz or higher, 10 of 61 (16.4%) patients (P ¼ .435).
421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 Q21 MHE on the Prognosis Based on MELD Score 439 Patients with a MELD score less than 10 and a normal 440 CFF score showed a survival rate of 94.5% (52 of 55 pa441 tients), and patients with a MELD score less than 10 and 442 MHE showed a survival rate of 91.9% (34 of 37 patients; 443 log-rank, 0.643; P ¼ .423). Among patients with a MELD 444 score of 15 or higher, MHE had an influence on long-term 445 survival. Those patients with a MELD score of 15 or 446 greater but with no MHE had a better survival rate (8 of 13 447 [61.5%] patients) compared with patients with MHE (2 of 448 12 [16.7%] patients) (log-rank, 5.883; P ¼ .015). Finally, 449 MHE also was able to predict survival in patients with MELD 450 scores of 10–15. In this group, patients with MHE had a poor 451 prognosis (12 of 27 [44.4%] patients) compared with pa452 tients without MHE (25 of 36 [69.4%] patients) (log-rank, 453 4.441; P ¼ .035). The log-rank value of these 3 groups 454 segregated with respect to the presence of MHE was 90.556 455 (P ¼ .0001) (Figure 3). 456 Figure 2. (A) Influence of CFF on survival in the estimation 457 cohort. (B) Influence of CFF on survival in the validation 458 cohort. Discussion 459 Our results showed that CFF, as a measure of MHE, had 460 an impact on long-term overall survival in 2 independent 461 462 463 Table 2.Univariable and Multivariable Analyses to Predict Long-Term Survival in the Estimation Cohort 464 Univariable 465 Q32 Q33 Multivariable analysisb Characteristic Survival (n ¼ 92) Mortality (n ¼ 25) analysis, P valuea 466 467 Sex distribution 468 Males 75% 72% .775 469 Age ± SD, y 56.5 ± 10.6 62.4 ± 10.5 .015 HR, 1.07; 95% CI, 1.02–1.12; P ¼ .009 MELD score ± SD 9.4 ± 4.1 11.4 ± 2.9 .020 HR, 1.40; 95% CI, 1.21–1.63; P ¼ .0001 470 Child–Pugh score 6.2 ± 1.5 6.4 ± 1.4 .513 471 Alcohol-related cirrhosis 53.3% 52% .899 472 Esophageal varices 71.7% 88% .140 473 Albumin level, mg/dL 3.7 ± 1.1 4.1 ± 0.7 .080 474 CFF < 39 Hz 32.4% 50% .024 HR, 4.36; 95% CI, 1.67–11.37; P ¼ .003 475 PHES < -4 23% 36% .097 476 477 a Univariable analysis was performed using the Student t test and the log-rank test. 478 b Multivariable analysis was performed using Cox regression. 479 480 FLA 5.4.0 DTD YGAST59968_proof 25 September 2015 11:22 am ce
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Figure 3. Impact of MHE in relation to the MELD score.
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cohorts of patients with cirrhosis who were followed up for more than 5 years. In addition, older age and lower MELD scores were associated independently with a poor prognosis. The debate continues regarding the most appropriate method(s) to detect MHE, especially between psychometric (ranging from PHES to computerized tests) and neurophysiological tests (eg, CFF). Conversely, the West Haven criteria and Glasgow coma scale have been used widely in determining overt HE staging. The concerns exist because patients with low-grade HE may be missed if not assessed systematically. It is believed that psychometric and neurophysiological methods are complementary because they explore different pathways and mechanisms of the disease. However, the spectrum of HE is a continuum and, sometimes, it is difficult to establish cut-off values between stages. For example, modified PHES17 and different cut-off values for CFF18 have been proposed. Specifically, PHES has been shown to be influenced by age, education level, and cultural issues. The detection of MHE is essential because of its relationship with falls,19 impairment of motor vehicle driving abilities,20 overt HE,21 and, now, survival. A few studies evaluating the impact of MHE on survival have been reported. Amodio et al22 reported a study on this topic. They enrolled 94 consecutive cirrhotic patients and 80 control individuals. Cognitive alterations were assessed using the NCT and a set of computerized psychometric tests. Of the tests used, Scan and Choice2 tests had prognostic value with respect to survival in the first year of follow-up evaluation (median follow-up period, 14.2 mo). Hartmann et al23 included 116 consecutive cirrhotic patients for a median follow-up period of 29 months (range, 1–49 mo), and assessed MHE using the NCT-A, the DST, and an
electroencephalogram. Their results showed that patients with MHE had more frequent HE events during follow-up evaluation, albeit overall survival rates were similar (P ¼ .26). In 2004, we evaluated 126 consecutive cirrhotic patients (median follow-up period, 25 mo) and assessed MHE using NCTs, the DST, and the block design test. Our results indicated that the presence of MHE was not related to survival (P ¼ .23). However, in multivariate analyses, patients with MHE and abnormal oral glutamine challenge had an increased mortality risk (HR, 5.5; 95% CI, 1.81–16.6; P ¼ .0039).24 Dhiman et al25 studied 104 consecutive cirrhotic patients (median follow-up period, 22 mo) and 83 healthy control subjects. MHE was diagnosed when PHES was -5 or less. In addition, an age-adjusted Z-score of -2 or less on the CFF was considered abnormal. MHE was associated with a poor prognosis in univariate analysis (39.1% vs 22.9%). However, MHE diagnosed using PHES needed to be modified (using receiver operating characteristic curves for best discrimination) to become an independent predictor of mortality in multivariate analysis (PHES -6; HR, 2.42; 95% CI, 1.01–5.77; P ¼ .046). Patidar et al26 assessed the impact of covert HE on overt HE, hospitalization, and death/ liver transplant over a follow-up period of 13.0 ± 14.6 months. A standard paper–pencil cognitive battery was administered to evaluate covert HE. The group of patients with covert HE had more deaths than the group without (17.9% vs 5.3%, respectively). This variable was related to death/transplant occurrence (HR, 3.4; 95% CI, 1.2–9.7; P < .05).26 An explanation for these discrepancies remains elusive, but certain biases may have a bearing, the first Q24 discrepancy was the diagnostic criteria used to define MHE, which were heterogeneous. We had used widely accepted methods such as PHES and CFF, which are continuous and
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dichotomous variables, respectively.27 However, other studies used only some tests from the PHES battery and, more importantly, did not apply the CFF test. The second discrepancy was the number of patients included in our study, which was significantly higher, and, taking into account both cohorts, would have highlighted any lack of statistical power. Third, a shorter follow-up period could have missed the middle- to long-term impact of MHE on survival (median follow-up period, 5 vs 2 y). Fourth, liver function; in our current study, we included patients at more advanced stages of liver disease (up to 40% of patients showed Child–Pugh B or C in both cohorts), which enabled more outcomes to register as being statistically significant. In the current study we identified subgroups of cirrhotic patients with extreme prognoses. First, patients with a MELD score less than 10 showed an excellent survival rate (>90% remained alive at the conclusion of the follow-up evaluation) regardless of the presence of MHE. Other investigators also have reported benefits of the MELD 10point cut-off value with respect to prognosis in cirrhotic patients. Wiesner et al28 observed that the group of patients with a MELD score of less than 10 had a 2% mortality rate at 3 months. Similarly, Jacob et al29 studied survival rates in 3838 patients after the first elective liver transplant. The patients were segregated according to their MELD scores (<10, 11–18, 19–24, 25–35, or >36). The 90-day survival rate was 92.6% in patients with a MELD score less than 10. Second, we found that CFF was critical in the prognosis of patients with a MELD score of 10 or higher. In patients with MELD scores of 10–15 and MELD scores of 15 or greater, patients with MHE (CFF < 39 Hz) had a poorer prognosis. Specifically, only 16% of patients with MHE and a MELD score of 15 or higher remained alive in the 5 years of followup evaluation. Of note is that patients with MELD scores of 10–15 and MHE showed a poorer survival rate than patients with a MELD score of 15 or higher without MHE (45% vs 69%). In clinical practice, subjects need to have a MELD score of at least 15 to be placed on the liver transplant waiting list (ie, patients who do not reach this cut-off value usually are not considered for a liver transplant). However, there are well-documented conditions that are not reflected clearly by the MELD score (eg, hepatocellular carcinoma30 and overt HE31). This observation has caused many investigators to try to incorporate other variables into the MELD score (eg, sodium concentrations and age).32 For example, Montagnese et al33 found that the addition of an electroencephalogram (indicative of the presence of HE) improved the prognostic accuracy of the MELD score. In our current study, we observed that patients with MELD scores of 10–15 (generally with no option of a liver transplant) with MHE, had more or less the same prognosis as patients placed on the liver transplant waiting list. Hence, this combination (MELD and MHE) enables a subgroup of patients to be identified who have a very high mortality risk, an even higher risk than patients with a MELD score of 15 or higher. The addition of MHE to the MELD score could enable the identification and selection of subgroups of patients who ought to be prioritized in the liver transplantation option, or referred to an appropriate prophylactic therapy.34,35
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This study had some limitations. First, we did not calculate the sample size. This study is a result of collecting Q27 cirrhotic populations from 4 different Spanish hospitals in clinical practice. As a result, the power to detect some meaningful effects (such as PHES on survival) might result from type II errors. However, the protracted follow-up evaluation could compensate, at least in part, for this drawback. Second, we found CFF superior to PHES in predicting survival, although this comparison was not an objective of the study. Therefore, this conclusion should be considered with caution. Third, some missing data are inevitable. However, these values were missing at random, and the problem was circumvented by using complete-case analysis. Data from this current study indicate the value of routine assessment of MHE in patients with cirrhosis. Specifically, our data showed the impact of MHE on survival. CFF appears to be the most suitable method to show this association. The influence of MHE, evaluated by CFF, adjusted for the MELD score could improve the prediction of survival in cirrhotic patients and, as such, the CFF test could help the physician in the decision-making processes with respect to prognosis in cirrhotic patients.
References 1. Bustamante J, Rimola A, Ventura PJ, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999;30:890–895. 2. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology 2014;60:715–735. 3. Das A, Dhiman RK, Saraswat VA, et al. Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. J Gastroenterol Hepatol 2001;16:531–535. 4. Romero-Gómez M, Ampuero J. Deciphering the spectrum of low-grade hepatic encephalopathy in clinical practice. Gastroenterology 2014;146:887–890. 5. Stewart CA, Smith GE. Minimal hepatic encephalopathy. Nat Clin Pract Gastroenterol Hepatol 2007;4:677–685. 6. Romero-Gomez M, Boza F, Garcia-Valdecasas MS, et al. Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 2001;96:2718–2723. 7. Bajaj JS, Saeian K, Schubert CM, et al. Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test. Hepatology 2009;50:1175–1183. 8. Kircheis G, Knoche A, Hilger N, et al. Hepatic encephalopathy and fitness to drive. Gastroenterology 2009; 137:1706–1715. 9. Román E, Córdoba J, Torrens M, et al. Minimal hepatic encephalopathy is associated with falls. Am J Gastroenterol 2011;106:476–482. 10. Goldberg DS, Olthoff KM. Standardizing MELD exceptions: current challenges and future directions. Curr Transplant Rep 2014;1:232–237. 11. Singal AK, Kamath PS. Model for end-stage liver disease. J Clin Exp Hepatol 2013;3:50–60.
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12. Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology 2013;57:1651–1653. 13. Grace ND, Groszmann RJ, Garcia-Tsao G, et al. Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology 1998;28:868–880. 14. Weissenborn K, Ennen JC, Schomerus H, et al. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001;34:768–773. 15. Kircheis G, Wettstein M, Timmermann L, et al. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 2002;35:357–366. 16. Reichenbach A, Fuchs U, Kasper M, et al. Hepatic retinopathy: morphological features of retinal glial (Müller) cells accompanying hepatic failure. Acta Neuropathol 1995;90:273–281. 17. Kircheis G, Hilger N, Häussinger D. Value of critical flicker frequency and psychometric hepatic encephalopathy score in diagnosis of low-grade hepatic encephalopathy. Gastroenterology 2014;146:961–969. 18. Torlot FJ, McPhail MJ, Taylor-Robinson SD. Metaanalysis: the diagnostic accuracy of critical flicker frequency in minimal hepatic encephalopathy. Aliment Pharmacol Ther 2013;37:527–536. 19. Soriano G, Román E, Córdoba J, et al. Cognitive dysfunction in cirrhosis is associated with falls: a prospective study. Hepatology 2012;55:1922–1930. 20. Felipo V, Urios A, Valero P, et al. Serum nitrotyrosine and psychometric tests as indicators of impaired fitness to drive in cirrhotic patients with minimal hepatic encephalopathy. Liver Int 2013;33:1478–1489. 21. Romero-Gómez M, Córdoba J, Jover R, et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology 2007;45:879–885. 22. Amodio P, Del Piccolo F, Marchetti P, et al. Clinical features and survival of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology 1999;29:1662–1667. 23. Hartmann IJ, Groeneweg M, Quero JC, et al. The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol 2000;95:2029–2034. 24. Romero-Gómez M, Grande L, Camacho I. Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy. Hepatology 2004; 39:939–943. 25. Dhiman RK, Kurmi R, Thumburu KK, et al. Diagnosis and prognostic significance of minimal hepatic encephalopathy in patients with cirrhosis of liver. Dig Dis Sci 2010; 55:2381–2390.
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26. Patidar KR, Thacker LR, Wade JB, et al. Covert hepatic encephalopathy is independently associated with poor survival and increased risk of hospitalization. Am J Gastroenterol 2014;109:1757–1763. 27. Mullen KD, Prakash RK. Management of covert hepatic encephalopathy. Clin Liver Dis 2012;16:91–93. 28. Wiesner R, Edwards E, Freeman R, et al. Model for endstage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91–96. 29. Jacob M, Copley LP, Lewsey JD, et al. Pretransplant MELD score and post liver transplantation survival in the UK and Ireland. Liver Transpl 2004;10:903–907. 30. Sharma P, Balan V, Hernández JL, et al. Liver transplantation for hepatocellular carcinoma: the MELD impact. Liver Transpl 2004;10:36–41. 31. Stewart CA, Malinchoc M, Kim WR, et al. Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease. Liver Transpl 2007; 13:1366–1371. 32. Luca A, Angermayr B, Bertolini G, et al. An integrated MELD model including serum sodium and age improves the prediction of early mortality in patients with cirrhosis. Liver Transpl 2007;13:1174–1180. 33. Montagnese S, De Rui M, Schiff S, et al. Prognostic benefit of the addition of a quantitative index of hepatic encephalopathy to the MELD score: the MELD-EEG. Liver Int 2015;35:58–64. 34. Romero-Gómez M, Montagnese S, Jalan R. Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure. J Hepatol 2015;62:437–447. 35. Ampuero J, Ranchal I, Nuñez D, et al. Metformin inhibits glutaminase activity and protects against hepatic encephalopathy. PLoS One 2012;7:e49279.
781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 Q28 Author names in bold designate shared co-first authorship. 816 Received April 22, 2015. Accepted July 17, 2015. 817 818 Reprint requests 819 Address requests for reprints to: Manuel Romero-Gómez, MD, PhD, Unit for the Clinical Management of Digestive Diseases and CIBERehd, Valme 820 University Hospital, Avenida de Bellavista s/n, 41014 Sevilla, Spain. e-mail: Q3 821 [email protected]; fax: (34) 955-015899. 822 Acknowledgments 823 Javier Ampuero and Manuel Romero-Gómez were responsible for the study design, drafting the manuscript, and statistical analyses and interpretation; 824 and Javier Ampuero, Macarena Simón, Carmina Montoliú, Rodrigo Jover, 825 Miguel Ángel Serra, and Juan Córdoba were responsible for data acquisition. 826 Conflicts of interest 827 Q4 The authors disclose no conflicts. 828 Funding 829 Q5 Q6 Writing support was provided by Peter R. Turner from Tscimed.com. 830 831 832 833 834 835 836 837 838 839 840
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61 62 63 64 65 66 67 68 Javier Ampuero,1 Macarena Simón,2 Carmina Montoliú,3 Rodrigo Jover,4 Miguel Ángel Serra,5 69 Juan Córdoba,2 and Manuel Romero-Gómez1 70 71 1 Unit for the Clinical Management of Digestive Diseases and CIBERehd, Valme University Hospital, Sevilla, Spain; 2 3 72 Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d’Hebrón, Barcelona, Spain; Instituto de Investigación 73 Sanitaria–INCLIVA, Valencia, Spain; 4Gastroenterology Department, Hospital General Universitario, Alicante, Spain; 5 Hepatology Unit, Hospital Clínico Universitario, Valencia, Spain 74 75 BACKGROUND & AIMS: Minimal hepatic encephalopathy outcomes of patients with specific MELD scores. The CFF could 76 (MHE) is associated with falls, traffic accidents, and overt HE. help physicians determine prognoses of patients with cirrhosis. 77 However, the association with survival is controversial. We 78 assessed the effects of MHE on the long-term survival of pa79 tients with cirrhosis. METHODS: We performed a prospective Keywords: PHES; Prognostic Factor; Mortality; Liver Fibrosis. 80 study of 117 consecutive patients with cirrhosis seen at a ter81 tiary hospital in Seville, Spain (estimation cohort), followed by a 82 epatic encephalopathy (HE) is one of the major Q9 Q10 83 validation study of 114 consecutive patients with cirrhosis seen Q11 complications of cirrhosis, affecting one third of at 4 hospitals in Spain from January 2004 through December 84 2007. Patients were examined every 6 months at outpatient cirrhotic patients. It has a relevant socioeconomic impact Q12 85 clinics through December 2013 (follow-up periods of 5 ± 2.8 y because HE reduces quality of life and is associated with a 86 and 4.4 ± 3.9 y for each group, respectively). Cirrhosis was higher mortality rate.1 As a consequence, the appropriate 87 identified by liver biopsy, ultrasound, endoscopic analysis, and scientific bodies (the American Association for the Study of 88 biochemical parameters. Liver dysfunction was determined Liver Diseases and the European Association for the Study 89 based on model for end-stage liver disease (MELD) and Child– of the Liver) released practice guidelines in 2014 for the 2 Pugh scores. All patients were administered the critical flicker management of HE. Furthermore, 30%–50% of cirrhotic Q13 90 91 frequency (CFF) test and psychometric hepatic encephalopathy patients showed minimal hepatic encephalopathy (MHE)3 92 scores were used to detect MHE. Survival curves were when tested by neuropsychological tests such as the Psy93 compared using the log-rank test and multivariable analysis chometric Hepatic Encephalopathy Score (PHES) or neuro94 was performed using Cox proportional hazards models. physiological methods such as critical flicker frequency 95 RESULTS: The distributions of Child–Pugh scores were as fol(CFF), representing the first stage in the HE spectrum.4 MHE 96 lows: 66% class A, 31% class B, and 3% class C in the estiis defined as the presence of cognitive abnormalities in 97 mation cohort, and 50% class A, 32% class B, and 18% class C in the validation cohort. In the estimation cohort, 24 of 35 patients with liver disease, which are not detected with the 98 patients (68.6%) with a CFF score less than 39 Hz survived for standard examinations, but rather is diagnosed only by us99 neuropsychological and neurophysiological 5 years, whereas 50 of 61 patients (82%) with a CFF score of ing sensitive 100 5 39 Hz or higher survived during the follow-up period (log-rank tests. MHE predicts the appearance of overt HE in cirrhotic 101 6 7,8 score, 5.07; P ¼ .024). Psychometric hepatic encephalopathy patients, impairs motor vehicle driving abilities, and in102 9 scores did not correlate with survival. In multivariable analysis, creases the risk of falling over. However, the relationship 103 older age (hazard ratio [HR], 1.07; 95% confidence interval [CI], with mortality has not been widely assessed. Conversely, the 104 1.02–1.12; P ¼ .009), CFF score less than 39 Hz (HR, 4.36; 95% model for end-stage liver disease (MELD) score quantifies 105 CI, 1.67–11.37; P ¼ .003), and MELD score (HR, 1.40; 95% CI, end-stage liver disease and is used widely as a criterion in 106 10 1.21–1.63; P ¼ .0001) were associated independently with liver transplant decision making. The MELD score com107 survival during the follow-up period. In the validation cohort, prises bilirubin level, creatinine level, and the institutional 108 CFF score less than 39 Hz and MELD score also were associated normalized ratio, but does not include clinical variables. Q14 109 with patient survival during the follow-up period. MHE had no Over the past decade, several modifications have been 110 effect on the survival of patients with MELD scores less than 10 proposed to improve and refine the MELD score.11 111 (among patients with CFF scores 39 Hz, 94.5% survived for 5 112 years vs 91.9% of patients with CFF scores <39 Hz; log-rank 113 score, 0.64; P ¼ .423). Fewer patients with MELD scores of 114 10–15 and MHE survived for 5 years (44.4%; 12 of 27) than Abbreviations used in this paper: CI, confidence interval; CFF, critical flicker frequency; DST, digit symbol test; HE, hepatic encephalopathy; HR, 115 those with MELD scores greater than 15 without MHE (61.5%; hazard ratio; MELD, model for end-stage liver disease; MHE, minimal 116 8 of 13) (P < .05). Only 2 of 12 patients (16.7%) with MELD hepatic encephalopathy; NCT, number connection test; PHES, Psycho117 scores of 15 or higher and MHE survived for 5 years (log-rank metric Hepatic Encephalopathy Score. 118 score, 90.56; P ¼ .0001). CONCLUSIONS: MHE is associated © 2015 by the AGA Institute 119 with a reduced 5-year survival rate of patients with cirrhosis. 0016-5085/$36.00 Evaluation of MHE could help predict survival times and 120 http://dx.doi.org/10.1053/j.gastro.2015.07.067
Minimal Hepatic Encephalopathy and Critical Flicker Frequency Are Associated With Survival of Patients With Cirrhosis
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The aims of the present study were to determine prospectively the clinical impact of MHE on long-term overall survival in patients with cirrhosis and, as well, to determine the influence of MHE on the MELD score to rationalize the liver transplantation waiting lists.
Materials and Methods Patient Selection We prospectively recruited 2 independent cohorts: (1) a single-centered estimation cohort (n ¼ 117) of consecutive cirrhotic patients from the Valme University Hospital, and (2) a multicenter validation cohort (n ¼ 114) of consecutive patients with cirrhosis from 4 Spanish hospitals (Figure 1). All patients were recruited between January 2004 and December 2007, and were followed up every 6 months in the outpatient clinics until December 2013. Cirrhosis was defined by liver biopsy, ultrasound, endoscopic analysis, and biochemical parameters. Liver dysfunction was evaluated by MELD and Child–Pugh scores. Exclusion criteria were as follows: age 18 years and younger; diagnosis of hepatocellular carcinoma before enrollment; patients with ongoing treatment for viral cirrhosis; history of recent (<3 mo) alcohol abuse; infection; recent (<6 wk) antibiotic use or gastrointestinal bleeding; and a history of recent (<6 wk) use of benzodiazepines, anti-epileptic, or psychotropic drugs. All patients were assessed with PHES and CFF, both to detect MHE. Of the patients, 5 were found to be almost illiterate and, hence, were unable to perform the PHES, 21 patients were unable to read or count correctly, and had inadequate eyesight (with or without correction spectacles) to be tested accurately with the CFF test. Patients underwent an upper gastrointestinal endoscopy to detect the presence of esophageal varices. All patients provided written informed consent for the collection and storage of peripheral blood mononuclear cells, as well as host DNA testing for research purposes consistent with the current study. All data, including clinical, demographic, and test results, were coded and deposited in the original clinical database. The protocol was approved by the ethics committees of the participating hospitals. The study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice.
Figure 1. Flow of participants in the study.
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Clinical End Points The main outcome of the current study was mortality-free survival. Our first aim was to evaluate the impact of MHE on long-term survival. Our second aim was to incorporate the routine MHE detection, controlling for MELD score, to improve survival prediction. The data from the 5 first years of follow-up evaluation were used to anticipate the requirement for liver transplantation in patients with poor prognosis. Other outcomes such as overt HE, variceal bleeding, ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome were recorded and clinically managed according to current guidelines.12,13
Encephalopathy Management MHE was based on PHES and CFF (Hepatonorm Analyzer; nevoLAB GmbH, Maierhöfen, Germany), which were measured at the same outpatient visit. Both tests were performed by the same expert operator in each center. Patients were classified as having MHE when the PHES score was below -4 points, or the CFF score was below the cut-off value (39 Hz).14,15 The PHES comprises the digit symbol test (DST), the number connection test A (NCT-A), the number connection test B (NCT-B), the serial dotting test, and the line drawing test. The retinal glial cells in patients with HE undergo similar changes to those seen in cerebral glial cells,16 and this observation forms the basis of CFF. The device uses a stepwise decrease in frequency from 60 to 25 Hz. Patients taking rifaximin, branched-chain amino acids, or ammonia decreasing drugs were excluded because these treatments could influence MHE values.
Statistical Analyses Statistical analyses and graphics were performed with SPSS (19.0; SPSS, Inc, Chicago, IL). Continuous variables are presented as means ± SD, whereas discrete outcomes are expressed as percentages. Comparisons between groups were made using the Mann–Whitney U test, the Student t test, or analysis of variance for continuous variables, and the chisquare test or the Fisher exact test (when expected values in any of the cells of a contingency table were less than 5) for categoric data. Survival curves were compared using the Kaplan–Meier method (log-rank test) because time to mortality is crucial in interpreting the results. Variables that showed significance at a P value less than .05 in univariable analysis were entered into backward logistic regression analysis. Collinearity between CFF and PHES with MELD was ruled out. The multivariable models were constructed sequentially with variables entered individually, and a significance level of a P value greater than .05 was used to remove the variables from the model (except age and sex, which were included in all the models as well as albumin and the presence of esophageal varices because these are well-documented predictors of survival in cirrhotic patients). The method used for missing data was complete-case analysis because statistical packages excluded individuals with any missing value. To address the first aim of the study, we analyzed the impact of MHE on longterm survival in the estimation cohort, and subsequently applied in the validation cohort. To address the second aim of the study, we assessed the influence of MHE added to the MELD score in the overall cohort, but excluded patients undergoing liver transplantation as a potential confounding variable. The MELD score was categorized into 3 groups. We established the
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first group as a MELD score of 10 based on the receiver operator characteristic analysis of our data (area under the receiver operator characteristic curve, 0.81; 95% confidence interval [CI], 0.75–0.88; P ¼ .0001) with a sensitivity of 88% and a specificity of 72%. A MELD score of 15 defined the second group according to the worldwide consensus for those patients who needed to be included on the liver transplant waiting list. The third group comprised those patients with a MELD score between 10 and 15.
Results Baseline Characteristics of the Cohorts
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In the estimation cohort, we enrolled 117 cirrhotic patients with different etiologies: alcohol 53% vs no alcohol 47%. Liver function was classified as follows: Child–Pugh A, 65.8%; Child–Pugh B, 30.8%; Child–Pugh C, 3.4%; and MELD scores (10 ± 4). In the estimation cohort, 15 of 117 (12.8%) patients had experienced a previous overt HE event, 30 of 117 (25.6%) had variceal bleeding, 62 of 117 (53%) had ascites, 6 of 117 (5.1%) had spontaneous bacterial peritonitis, and 5 of 117 (4.3%) had hepatorenal syndrome at the time of enrollment. Esophageal varices were present in 88 of 117 (75.2%) patients. CFF was pathologic in 36.5% and PHES was pathologic in 25.9% of patients. These patients were followed up for 5 ± 2.8 years (Table 1). The validation cohort had 114 cirrhotic patients of different etiologies: alcohol 43% vs nonalcohol 57%. Liver function was classified as follows: Child–Pugh A, 50%; Child–Pugh B, 31.6%; Child–Pugh C, 18.4%; and MELD scores (12 ± 5.7). Within this cohort, 19 of 114 (16.7%) had experienced a previous overt HE event at the time of enrollment. Esophageal varices were present in 66 of 96 (68.8%) patients. CFF was pathologic in 47.4%, and PHES was present in 29.8% of patients. These patients were followed up for 4.4 ± 3.9 years.
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MHE and Survival In the estimation cohort, we found that a CFF score less than 39 Hz was related to lower survival rates (24 of 35; 68.6%) than a CFF of 39 Hz or greater (50 of 61; 82%) patients (log-rank, 5.073; P ¼ .024) (Figure 2A). An altered PHES was not related to a poorer prognosis by the end of the follow-up period (PHES < -4: 20 of 29 [69%] vs PHES -4: 67 of 83 [80.7%] patients; log-rank: 2.762; P ¼ .097). Other variables associated with survival were age and MELD score. In multivariable analysis, older age (hazard ratio [HR], 1.07; 95% CI, 1.02–1.12; P ¼ .009), CFF score less than 39 Hz (HR, 4.36; 95% CI, 1.67–11.37; P ¼ .003), and MELD score (HR, 1.40; 95% CI, 1.21–1.63; P ¼ .0001) were independent variables associated with impaired survival (Table 2). In the validation cohort, a CFF score less than 39 Hz was related to a poor prognosis by the end of the followup period (31 of 54; 57.4%) compared with a CFF score of 39 Hz or greater (42 of 60; 70%) patients (log-rank, 4.752; P ¼ .029) (Figure 2B). Age, MELD score, and albumin level also were associated with survival in univariable analysis. In multivariable analysis adjusted for sex, age, and albumin level, a CFF score less than 39 Hz (HR, 2.29; 95% CI, 1.28–4.08; P ¼ .005), and the MELD score (HR, 1.07; 95% CI, 1.03–1.11; P ¼ .0001) were independent variables associated with impaired survival.
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MHE and Cirrhosis Outcomes The CFF score predicted the appearance of overt HE during the follow-up evaluation, results in the estimation cohort were as follows: CFF score less than 39 Hz, 13 of 35 (37.1%) vs CFF score of 39 Hz or higher, 15 of 61 (24.6%) patients (log-rank, 4.896; P ¼ .027); and results in the validation cohort were as follows: CFF score less than 39 Hz, 21 of 54 (38.9%) vs CFF score of 39 Hz or higher, 11 of 60 (18.3%) patients (log-rank, 9.576; P ¼ .002). Overt HE was
Table 1.Baseline Characteristics and Outcomes in the Estimation and Validation Cohorts During Follow-Up Evaluation
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Characteristic
Estimation cohort (N ¼ 117)
Validation cohort (N ¼ 114)
Sex distribution, males Age ± SD, y MELD score ± SD Child–Pugh score, A/B/C Alcohol-related cirrhosis Esophageal varices Previous HE event Previous variceal bleeding Previous ascites Previous SBP Previous hepatorenal syndrome CFF < 39 Hz PHES < -4 Overt HE Liver transplantation All-cause mortality Liver-related mortality
74.4% (87/117) 57.8 ± 10.8 9.8 ± 4 77/36/4 53% (62/117) 75.2% (88/117) 12.8% (15/117) 25.6% (30/117) 53% (62/117) 5.1% (6/117) 4.3% (5/117) 36.5% (35/96) 25.9% (29/112) 30.8% (36/117) 14.5% (17/117) 21.4% (25/117) 72% (18/25)
71.9% (82/114) 57.3 ± 11.1 12 ± 5.6 57/36/21 43% (49/114) 68.8% (66/96) 16.7% (19/114)
47.4% 29.8% 28.1% 14.9% 36% 65.8%
(54/114) (34/114) (32/114) (17/114) (41/114) (27/41)
NOTE. Previous cirrhosis outcomes were not obtained for the validation cohort because this was not the aim of the study. SBP, spontaneous bacterial peritonitis.
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associated with survival in the estimation (41.7% [15 of 36] vs 12.3% [10 of 81]; P ¼ .0001) as well as the validation cohort (50% [16 of 32] vs 30.5% [25 of 82]; P ¼ .050). However, these test results were not related to variceal bleeding: CFF score less than 39 Hz, 12 of 35 (34.3%) vs CFF score of 39 Hz or higher, 17 of 61 (27.9%) patients (P ¼ .510); ascites: CFF score less than 39 Hz: 14 of 35 (40%) vs CFF score of 39 Hz or higher, 21 of 61 (34.4%) patients (P ¼ .585); spontaneous bacterial peritonitis: CFF score less than 39 Hz, 4 of 35 (11.4%) vs CFF score of 39 Hz or higher, 3 of 61 (4.9%) patients (P ¼ .253); hepatorenal syndrome: CFF score less than 39 Hz, 7 of 35 (20%) vs CFF score of 39 Hz or greater, 7 of 61 (11.5%) patients (P ¼ .255); or hepatocellular carcinoma: CFF score less than 39 Hz, 8 of 35 (22.9%) vs CFF score of 39 Hz or higher, 10 of 61 (16.4%) patients (P ¼ .435).
421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 Q21 MHE on the Prognosis Based on MELD Score 439 Patients with a MELD score less than 10 and a normal 440 CFF score showed a survival rate of 94.5% (52 of 55 pa441 tients), and patients with a MELD score less than 10 and 442 MHE showed a survival rate of 91.9% (34 of 37 patients; 443 log-rank, 0.643; P ¼ .423). Among patients with a MELD 444 score of 15 or higher, MHE had an influence on long-term 445 survival. Those patients with a MELD score of 15 or 446 greater but with no MHE had a better survival rate (8 of 13 447 [61.5%] patients) compared with patients with MHE (2 of 448 12 [16.7%] patients) (log-rank, 5.883; P ¼ .015). Finally, 449 MHE also was able to predict survival in patients with MELD 450 scores of 10–15. In this group, patients with MHE had a poor 451 prognosis (12 of 27 [44.4%] patients) compared with pa452 tients without MHE (25 of 36 [69.4%] patients) (log-rank, 453 4.441; P ¼ .035). The log-rank value of these 3 groups 454 segregated with respect to the presence of MHE was 90.556 455 (P ¼ .0001) (Figure 3). 456 Figure 2. (A) Influence of CFF on survival in the estimation 457 cohort. (B) Influence of CFF on survival in the validation 458 cohort. Discussion 459 Our results showed that CFF, as a measure of MHE, had 460 an impact on long-term overall survival in 2 independent 461 462 463 Table 2.Univariable and Multivariable Analyses to Predict Long-Term Survival in the Estimation Cohort 464 Univariable 465 Q32 Q33 Multivariable analysisb Characteristic Survival (n ¼ 92) Mortality (n ¼ 25) analysis, P valuea 466 467 Sex distribution 468 Males 75% 72% .775 469 Age ± SD, y 56.5 ± 10.6 62.4 ± 10.5 .015 HR, 1.07; 95% CI, 1.02–1.12; P ¼ .009 MELD score ± SD 9.4 ± 4.1 11.4 ± 2.9 .020 HR, 1.40; 95% CI, 1.21–1.63; P ¼ .0001 470 Child–Pugh score 6.2 ± 1.5 6.4 ± 1.4 .513 471 Alcohol-related cirrhosis 53.3% 52% .899 472 Esophageal varices 71.7% 88% .140 473 Albumin level, mg/dL 3.7 ± 1.1 4.1 ± 0.7 .080 474 CFF < 39 Hz 32.4% 50% .024 HR, 4.36; 95% CI, 1.67–11.37; P ¼ .003 475 PHES < -4 23% 36% .097 476 477 a Univariable analysis was performed using the Student t test and the log-rank test. 478 b Multivariable analysis was performed using Cox regression. 479 480 FLA 5.4.0 DTD YGAST59968_proof 25 September 2015 11:22 am ce
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Figure 3. Impact of MHE in relation to the MELD score.
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cohorts of patients with cirrhosis who were followed up for more than 5 years. In addition, older age and lower MELD scores were associated independently with a poor prognosis. The debate continues regarding the most appropriate method(s) to detect MHE, especially between psychometric (ranging from PHES to computerized tests) and neurophysiological tests (eg, CFF). Conversely, the West Haven criteria and Glasgow coma scale have been used widely in determining overt HE staging. The concerns exist because patients with low-grade HE may be missed if not assessed systematically. It is believed that psychometric and neurophysiological methods are complementary because they explore different pathways and mechanisms of the disease. However, the spectrum of HE is a continuum and, sometimes, it is difficult to establish cut-off values between stages. For example, modified PHES17 and different cut-off values for CFF18 have been proposed. Specifically, PHES has been shown to be influenced by age, education level, and cultural issues. The detection of MHE is essential because of its relationship with falls,19 impairment of motor vehicle driving abilities,20 overt HE,21 and, now, survival. A few studies evaluating the impact of MHE on survival have been reported. Amodio et al22 reported a study on this topic. They enrolled 94 consecutive cirrhotic patients and 80 control individuals. Cognitive alterations were assessed using the NCT and a set of computerized psychometric tests. Of the tests used, Scan and Choice2 tests had prognostic value with respect to survival in the first year of follow-up evaluation (median follow-up period, 14.2 mo). Hartmann et al23 included 116 consecutive cirrhotic patients for a median follow-up period of 29 months (range, 1–49 mo), and assessed MHE using the NCT-A, the DST, and an
electroencephalogram. Their results showed that patients with MHE had more frequent HE events during follow-up evaluation, albeit overall survival rates were similar (P ¼ .26). In 2004, we evaluated 126 consecutive cirrhotic patients (median follow-up period, 25 mo) and assessed MHE using NCTs, the DST, and the block design test. Our results indicated that the presence of MHE was not related to survival (P ¼ .23). However, in multivariate analyses, patients with MHE and abnormal oral glutamine challenge had an increased mortality risk (HR, 5.5; 95% CI, 1.81–16.6; P ¼ .0039).24 Dhiman et al25 studied 104 consecutive cirrhotic patients (median follow-up period, 22 mo) and 83 healthy control subjects. MHE was diagnosed when PHES was -5 or less. In addition, an age-adjusted Z-score of -2 or less on the CFF was considered abnormal. MHE was associated with a poor prognosis in univariate analysis (39.1% vs 22.9%). However, MHE diagnosed using PHES needed to be modified (using receiver operating characteristic curves for best discrimination) to become an independent predictor of mortality in multivariate analysis (PHES -6; HR, 2.42; 95% CI, 1.01–5.77; P ¼ .046). Patidar et al26 assessed the impact of covert HE on overt HE, hospitalization, and death/ liver transplant over a follow-up period of 13.0 ± 14.6 months. A standard paper–pencil cognitive battery was administered to evaluate covert HE. The group of patients with covert HE had more deaths than the group without (17.9% vs 5.3%, respectively). This variable was related to death/transplant occurrence (HR, 3.4; 95% CI, 1.2–9.7; P < .05).26 An explanation for these discrepancies remains elusive, but certain biases may have a bearing, the first Q24 discrepancy was the diagnostic criteria used to define MHE, which were heterogeneous. We had used widely accepted methods such as PHES and CFF, which are continuous and
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dichotomous variables, respectively.27 However, other studies used only some tests from the PHES battery and, more importantly, did not apply the CFF test. The second discrepancy was the number of patients included in our study, which was significantly higher, and, taking into account both cohorts, would have highlighted any lack of statistical power. Third, a shorter follow-up period could have missed the middle- to long-term impact of MHE on survival (median follow-up period, 5 vs 2 y). Fourth, liver function; in our current study, we included patients at more advanced stages of liver disease (up to 40% of patients showed Child–Pugh B or C in both cohorts), which enabled more outcomes to register as being statistically significant. In the current study we identified subgroups of cirrhotic patients with extreme prognoses. First, patients with a MELD score less than 10 showed an excellent survival rate (>90% remained alive at the conclusion of the follow-up evaluation) regardless of the presence of MHE. Other investigators also have reported benefits of the MELD 10point cut-off value with respect to prognosis in cirrhotic patients. Wiesner et al28 observed that the group of patients with a MELD score of less than 10 had a 2% mortality rate at 3 months. Similarly, Jacob et al29 studied survival rates in 3838 patients after the first elective liver transplant. The patients were segregated according to their MELD scores (<10, 11–18, 19–24, 25–35, or >36). The 90-day survival rate was 92.6% in patients with a MELD score less than 10. Second, we found that CFF was critical in the prognosis of patients with a MELD score of 10 or higher. In patients with MELD scores of 10–15 and MELD scores of 15 or greater, patients with MHE (CFF < 39 Hz) had a poorer prognosis. Specifically, only 16% of patients with MHE and a MELD score of 15 or higher remained alive in the 5 years of followup evaluation. Of note is that patients with MELD scores of 10–15 and MHE showed a poorer survival rate than patients with a MELD score of 15 or higher without MHE (45% vs 69%). In clinical practice, subjects need to have a MELD score of at least 15 to be placed on the liver transplant waiting list (ie, patients who do not reach this cut-off value usually are not considered for a liver transplant). However, there are well-documented conditions that are not reflected clearly by the MELD score (eg, hepatocellular carcinoma30 and overt HE31). This observation has caused many investigators to try to incorporate other variables into the MELD score (eg, sodium concentrations and age).32 For example, Montagnese et al33 found that the addition of an electroencephalogram (indicative of the presence of HE) improved the prognostic accuracy of the MELD score. In our current study, we observed that patients with MELD scores of 10–15 (generally with no option of a liver transplant) with MHE, had more or less the same prognosis as patients placed on the liver transplant waiting list. Hence, this combination (MELD and MHE) enables a subgroup of patients to be identified who have a very high mortality risk, an even higher risk than patients with a MELD score of 15 or higher. The addition of MHE to the MELD score could enable the identification and selection of subgroups of patients who ought to be prioritized in the liver transplantation option, or referred to an appropriate prophylactic therapy.34,35
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This study had some limitations. First, we did not calculate the sample size. This study is a result of collecting Q27 cirrhotic populations from 4 different Spanish hospitals in clinical practice. As a result, the power to detect some meaningful effects (such as PHES on survival) might result from type II errors. However, the protracted follow-up evaluation could compensate, at least in part, for this drawback. Second, we found CFF superior to PHES in predicting survival, although this comparison was not an objective of the study. Therefore, this conclusion should be considered with caution. Third, some missing data are inevitable. However, these values were missing at random, and the problem was circumvented by using complete-case analysis. Data from this current study indicate the value of routine assessment of MHE in patients with cirrhosis. Specifically, our data showed the impact of MHE on survival. CFF appears to be the most suitable method to show this association. The influence of MHE, evaluated by CFF, adjusted for the MELD score could improve the prediction of survival in cirrhotic patients and, as such, the CFF test could help the physician in the decision-making processes with respect to prognosis in cirrhotic patients.
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12. Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology 2013;57:1651–1653. 13. Grace ND, Groszmann RJ, Garcia-Tsao G, et al. Portal hypertension and variceal bleeding: an AASLD single topic symposium. Hepatology 1998;28:868–880. 14. Weissenborn K, Ennen JC, Schomerus H, et al. Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001;34:768–773. 15. Kircheis G, Wettstein M, Timmermann L, et al. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 2002;35:357–366. 16. Reichenbach A, Fuchs U, Kasper M, et al. Hepatic retinopathy: morphological features of retinal glial (Müller) cells accompanying hepatic failure. Acta Neuropathol 1995;90:273–281. 17. Kircheis G, Hilger N, Häussinger D. Value of critical flicker frequency and psychometric hepatic encephalopathy score in diagnosis of low-grade hepatic encephalopathy. Gastroenterology 2014;146:961–969. 18. Torlot FJ, McPhail MJ, Taylor-Robinson SD. Metaanalysis: the diagnostic accuracy of critical flicker frequency in minimal hepatic encephalopathy. Aliment Pharmacol Ther 2013;37:527–536. 19. Soriano G, Román E, Córdoba J, et al. Cognitive dysfunction in cirrhosis is associated with falls: a prospective study. Hepatology 2012;55:1922–1930. 20. Felipo V, Urios A, Valero P, et al. Serum nitrotyrosine and psychometric tests as indicators of impaired fitness to drive in cirrhotic patients with minimal hepatic encephalopathy. Liver Int 2013;33:1478–1489. 21. Romero-Gómez M, Córdoba J, Jover R, et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology 2007;45:879–885. 22. Amodio P, Del Piccolo F, Marchetti P, et al. Clinical features and survival of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests. Hepatology 1999;29:1662–1667. 23. Hartmann IJ, Groeneweg M, Quero JC, et al. The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol 2000;95:2029–2034. 24. Romero-Gómez M, Grande L, Camacho I. Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy. Hepatology 2004; 39:939–943. 25. Dhiman RK, Kurmi R, Thumburu KK, et al. Diagnosis and prognostic significance of minimal hepatic encephalopathy in patients with cirrhosis of liver. Dig Dis Sci 2010; 55:2381–2390.
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26. Patidar KR, Thacker LR, Wade JB, et al. Covert hepatic encephalopathy is independently associated with poor survival and increased risk of hospitalization. Am J Gastroenterol 2014;109:1757–1763. 27. Mullen KD, Prakash RK. Management of covert hepatic encephalopathy. Clin Liver Dis 2012;16:91–93. 28. Wiesner R, Edwards E, Freeman R, et al. Model for endstage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91–96. 29. Jacob M, Copley LP, Lewsey JD, et al. Pretransplant MELD score and post liver transplantation survival in the UK and Ireland. Liver Transpl 2004;10:903–907. 30. Sharma P, Balan V, Hernández JL, et al. Liver transplantation for hepatocellular carcinoma: the MELD impact. Liver Transpl 2004;10:36–41. 31. Stewart CA, Malinchoc M, Kim WR, et al. Hepatic encephalopathy as a predictor of survival in patients with end-stage liver disease. Liver Transpl 2007; 13:1366–1371. 32. Luca A, Angermayr B, Bertolini G, et al. An integrated MELD model including serum sodium and age improves the prediction of early mortality in patients with cirrhosis. Liver Transpl 2007;13:1174–1180. 33. Montagnese S, De Rui M, Schiff S, et al. Prognostic benefit of the addition of a quantitative index of hepatic encephalopathy to the MELD score: the MELD-EEG. Liver Int 2015;35:58–64. 34. Romero-Gómez M, Montagnese S, Jalan R. Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure. J Hepatol 2015;62:437–447. 35. Ampuero J, Ranchal I, Nuñez D, et al. Metformin inhibits glutaminase activity and protects against hepatic encephalopathy. PLoS One 2012;7:e49279.
781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 Q28 Author names in bold designate shared co-first authorship. 816 Received April 22, 2015. Accepted July 17, 2015. 817 818 Reprint requests 819 Address requests for reprints to: Manuel Romero-Gómez, MD, PhD, Unit for the Clinical Management of Digestive Diseases and CIBERehd, Valme 820 University Hospital, Avenida de Bellavista s/n, 41014 Sevilla, Spain. e-mail: Q3 821 [email protected]; fax: (34) 955-015899. 822 Acknowledgments 823 Javier Ampuero and Manuel Romero-Gómez were responsible for the study design, drafting the manuscript, and statistical analyses and interpretation; 824 and Javier Ampuero, Macarena Simón, Carmina Montoliú, Rodrigo Jover, 825 Miguel Ángel Serra, and Juan Córdoba were responsible for data acquisition. 826 Conflicts of interest 827 Q4 The authors disclose no conflicts. 828 Funding 829 Q5 Q6 Writing support was provided by Peter R. Turner from Tscimed.com. 830 831 832 833 834 835 836 837 838 839 840
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