LIVER TRANSPLANTATION 20:14541461, 2014

ORIGINAL ARTICLE

Hepatic Encephalopathy Is Associated With

Significantly Increased Mortality Among
Patients Awaiting Liver Transplantation
Robert J. Wong,1,2 Robert G. Gish,3,4 and Aijaz Ahmed1
Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA;
2
Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto,
CA; 3Robert G. Gish Consultants LLC, La Jolla, CA; and 4Hepatitis B Foundation, Doylestown, PA

The prioritization of liver transplantation (LT) for patients with end-stage liver disease uses the Model for End-Stage Liver
Disease (MELD), which attempts to identify the sickest patients and thereby those who are in greatest need for LT. Hepatic
encephalopathy (HE) is not included in MELD, and severity of liver disease and risk of wait-list removal or wait-list death
may be underestimated by MELD in patients with HE. Using United Network for Organ Sharing registry data, we evaluated
the impact of HE on 90-day wait-list survival among adult LT wait-list registrants in the United States from 2003 to 2012.
Survival was stratified by HE severity (none, grade 1-2, grade 3-4) and MELD. There were 84,947 new LT wait-list registrants during the study period; 36.8% had no HE, 57.4% had grade 1-2 HE, and 5.9% had grade 3-4 HE. Ninety-day waitlist mortality was significantly higher among patients with grade 3-4 HE compared with patients with grade 1-2 HE or no HE
(24.4% versus 6.8% versus 3.5%; P < 0.001). When stratified by MELD, patients with grade 3-4 HE had 90-day wait-list
mortality similar to that of nonencephalopathic patients with MELD scores 6-7 points higher. With the multivariate Cox proportional hazards model, patients with grade 3-4 HE had 66% greater risk of 90-day mortality than patients without HE (hazard ratio 5 1.66, 95% CI 5 1.45-1.90; P < 0.001). The inclusion of HE severity in MELD improved the area under receiver
operating curve for predicting 90-day wait-list survival from 0.6508 to 0.6863. In conclusion, grade 3-4 HE at time of wait-list
registration significantly increases 90-day wait-list mortality independent of MELD score. Incorporating HE in the assessment of LT priority may improve prognostication of liver disease severity and prioritization for LT. Liver Transpl 20:1454C 2014 AASLD.
1461, 2014. V
Received April 7, 2014; accepted August 10, 2014.
Chronic liver disease is a leading cause of morbidity
and mortality in the United States.1 Progressive
hepatic fibrosis among patients with chronic liver disease leads to cirrhosis and its complications, including hepatocellular carcinoma (HCC) and end-stage
liver disease.2-4 Liver transplantation (LT) is a curative
option with 5-year post-LT survival greater than
80%.5 However, the growing number of patients

awaiting LT has far outpaced the availability of donor

livers to be allocated for LT in the United States6,7
The implementation of the Model for End-Stage
Liver Disease (MELD) score in 2002 was an attempt to
institute an objective system by which to prioritize
patients for LT.8,9 The MELD score incorporates objective measures of serum bilirubin, creatinine, and
international normalized ratio (INR) to prioritize

Additional Supporting Information may be found in the online version of this article.
Abbreviations: AUROC, area under the receiver operating curve; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HE,
hepatic encephalopathy; HR, hazard ratio; INR, international normalized ratio; ln, natural logarithm; LT, liver transplantation;
MELD, Model for End-Stage Liver Disease; TIPS, transjugular intrahepatic portosystemic shunt; UNOS/OPTN, United Network for
Organ Sharing/Organ Procurement and Transplantation Network.
Potential conflict of interest: Nothing to report.
Address reprint requests to Robert J. Wong, M.D., M.S., Division of Gastroenterology and Hepatology, Stanford University School of Medicine,
300 Pasteur Drive, Always Building, Suite M-211, Stanford, CA 94305. Telephone: 650-721-6190; FAX: 650-723-5488;
E-mail: rwong123@stanford.edu
DOI 10.1002/lt.23981
View this article online at wileyonlinelibrary.com.
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

C 2014 American Association for the Study of Liver Diseases.

V

LIVER TRANSPLANTATION, Vol. 20, No. 12, 2014

patients awaiting LT. In addition to the MELD score,

hyponatremia has also been shown to be an important predictor of mortality among patients with cirrhosis.10-13 With the concept of providing LT to patients
who are the sickest first and thereby benefiting the
sickest the most, LT is offered to patients with the
highest MELD scores first. However, hepatic encephalopathy (HE), a marker of hepatic decompensation, is
not included in the MELD scoring system, and several
studies have raised concern that the MELD score
underestimates the risk of mortality among patients
with HE.14-19 In addition, HE may not correlate well
with MELD across the range of MELD scores, and
patients with HE may not receive needed LT in a
timely manner under the current MELD scoring
system.14,15
In an effort to assess the impact of HE on LT waitlist mortality, we performed a retrospective cohort
study using 10 years of MELD-era data from a
population-based registry of all adult LT wait-list
registrants in the United States. We hypothesize that
HE will be associated with significantly increased 90day wait-list mortality independent of MELD scores.

PATIENTS AND METHODS

Study Population
Adult men and women (age >18 years) who were registered on the wait-list for LT in the United States
from January 1, 2003, to December 31, 2012, were
evaluated with data from the United Network for
Organ Sharing and Organ Procurement and Transplantation Network (UNOS/OPTN) registry. Our target
population consisted of patients with chronic liver disease awaiting LT. Patients who were listed for LT secondary to acute liver failure were excluded. The
prioritization of LT among patients with concurrent
HCC in the United States incorporates an exception
policy, such that patients with HCC within defined
criteria are allocated additional points to their MELD
score by regional transplant review boards, thereby
increasing their priority and probability of receiving
LT. The basis for this policy in part reflects the understanding that MELD score alone does not accurately
predict 90-day mortality among patients with concurrent HCC. For this reason, patients with HCC were
also excluded from our analyses.
MELD scores at the time of wait-list registration and
at the time of transplantation if LT was performed
were calculated for each individual. MELD scores
were calculated with standard formulae that incorporate the natural logarithms (ln) of INR, bilirubin, and
creatinine: 11.2 3 ln(INR) 1 9.57 3 ln (creatinine, in
milligrams per deciliter) 1 3.78 3 ln (bilirubin, in
milligrams per deciliter) 1 6.43, with a lower limit of 1
for all variables and an upper limit of 4 for creatinine.
Patients on hemodialysis are given a creatinine score
of 4. The grading of HE severity was based on West
Haven Criteria (grade 1 5 trivial lack of awareness,
euphoria or anxiety, shortened attention span,

WONG, GISH, AND AHMED 1455

impaired performance of addition or subtraction;

grade 2 5 lethargy or apathy, minimal disorientation
for time or place, subtle personality change, inappropriate behavior; grade 3 5 somnolence to semistupor
but responsive to verbal stimuli, confusion, gross disorientation; grade 4 5 coma (unresponsive to verbal or
noxious stimuli).16 Severity of HE (no HE, grade 1-2
HE, grade 3-4 HE) at time of wait-list registration and
at time of LT among transplant recipients were documented in the UNOS registry and relied on review of
clinical medical records to determine the most
recently documented grade of HE prior to wait-list
registration. Treatment for HE was not captured in
the UNOS registry data. The outcome for patients on
the LT wait list (ie, death, receipt of liver transplant,
or removal from wait list for other reasons) allowed
the calculation of our primary outcome, 90-day mortality among wait-listed patients. This outcome is
commonly used to evaluate LT wait-list mortality.

Statistical Analysis
Descriptive statistics were stratified by severity of HE
and presented as proportion (%) and frequency (N) for
categorical variables, mean and standard deviation
(SD) for normally distributed continuous variables,
and median and range for nonnormally distributed
variables. Comparisons between groups were performed with chi-square testing and analysis of variance methods. Kaplan-Meier methods were used to
evaluate our primary outcome of 90-day wait-list mortality. Stratification by MELD score and degree of HE
was applied in an attempt to determine whether the
increased mortality associated with HE was dependent on MELD score at time of wait-list registration. In
other words, for each MELD score (6-40), we calculated 90-day wait-list mortality for patients with no
HE, grade 1-2 HE, and grade 3-4 HE. To determine
whether there was a statistically significant nonlinear
relationship between severity of HE and 90-day waitlist mortality, we used a second-order polynomial
(quadratic) model to compare the graphic function
represented by each category of HE. The resulting
smooth curves depicted the relationship between
severity of HE and 90-day wait-list mortality for individual MELD scores. Multivariate Cox proportional
hazards models were used to evaluate the association
between HE and 90-day wait-list mortality. Forward
stepwise regression methods included variables that
satisfied biological priori (eg, age, sex) and those that
demonstrated significant associations in the univariate models (P < 0.10). The final multivariate model
was adjusted for sex, age, race/ethnicity, etiology of
liver disease [hepatitis C virus (HCV) versus nonHCV], MELD score, ascites, serum albumin, serum
sodium, year of wait-list registration, and HE. Statistical significance was met with a two-tailed P value
<0.05. We also performed additional regression analyses to compare the area under the receiver operating
curve (AUROC) for MELD alone versus the inclusion
of HE into the MELD score at predicting 90-day wait-

1456 WONG, GISH, AND AHMED

LIVER TRANSPLANTATION, December 2014

TABLE 1. Demographic and Clinical Characteristics of Patients on the LT Wait List

No HE

Male sex
Race/ethnicity
Non-Hispanic white
Black
Hispanic
Asian
Age (years; mean 6 SD)
MELD (mean 6 SD)
HCV
Ascites
Albumin (g/dL; mean 6 SD)
Sodium (mEq/L; mean 6 SD)

Grade 1-2 HE

Grade 3-4 HE

Percentage

Percentage

Percentage

P Value

61.8

19,315

65.0

31,658

63.0

3,142

<0.001
<0.001

72.3
9.9
13.5
4.3
51.7 6 11.3
15.5 6 7.1
43.9
55.2
3.1 6 0.7
136.7 6 4.3

22,394
3072
4189
1328

75.1
7.3
15.0
2.7
53.7 6 9.0
18.3 6 8.1
47.0
91.3
2.9 6 0.7
135.5 6 4.9

36,191
3495
7,227
1303

73.5
9.3
13.8
3.4
53.0 6 9.6
27.0 6 9.6
44.1
95.1
2.9 6 0.7
135.8 6 6.4

3617
457
681
167

10,175
17,237

19,610
44,502

1779
4739

<0.001
<0.001
<0.001
<0.001
<0.001
0.01

TABLE 2. Distribution of HE Severity at Time of Wait-List Registration and at Time of LT

Wait-List Registration
HE severity
No HE
Grade 1-2
Grade 3-4

Liver Transplantation

Percentage

Percentage

34.7
58.3
7.0

14,407
24,178
2898

30.6
58.2
11.3

12,694
24,160
4629

list survival. All statistical analyses were performed in

the Stata statistical package (version 10; Stata Corporation, College Station, TX) and Prism statistical software (version 6.0; GraphPad Software, Inc., La Jolla,
CA).

RESULTS
Characteristics of the Study Cohort
From January 1, 2003, to December 31, 2012, there
were 84,947 new LT wait-list registrants, among
whom 36.8% (n 5 31,239) had no HE, 57.4%
(n 5 48,722) had grade 1-2 HE, and 5.9% (n 5 4986)
had grade 3-4 HE. Although the majority of wait-list
registrants were men, there were significantly fewer
men in the no-HE group compared with grade 1-2 HE
or grade 3-4 HE cohorts (Table 1). Non-Hispanic
whites and Hispanics were more likely to have grade
1-2 HE at time of wait-list registration, whereas
blacks and Asians were more likely to have no HE or
grade 3-4 HE. The mean age was significantly higher
for patients with HE compared with those with no HE
(grade 3-4 HE 5 53.0 6 9.6 years versus grade 1-2
HE 5 53.7 6 9.0 years versus no HE 5 51.7 6 11.3
years; P < 0.001). In addition, patients with more
severe HE at time of wait-list registration had higher
mean MELD scores (grade 3-4 HE 5 27.0 6 9.6 versus
grade 1-2 HE 5 18.3 6 8.1 versus no HE 5 15.5 6 7.1;
P < 0.001). Patients with more severe HE also had significantly higher rates of ascites and lower serum

albumin (Table 1). Although the severity of HE among

LT wait-list patients was provided at time of wait-list
registration, additional time points documenting progression or improvement in HE were not available in
the registry. However, among patients who underwent
LT, HE severity at time of LT was documented. We
performed a subanalysis to determine the change in
HE severity from time of wait-list registration to time
of LT (Tables 2 and 3). Among patients with no HE at
registration, 32.1% (n 5 4627) had increased HE
severity at time of LT, whereas the remainder continued to have no HE (Table 3). Among patients with
grade 1-2 HE at registration, 8.9% (n 5 2157) had
increased HE severity, 11.2% (n5 2707) had
decreased HE severity, and 79.9% (n 5 19,314) had
unchanged HE severity at time of LT. Among patients
with grade 3-4 HE at registration, 35.9% (n5 1041)
had decreased HE severity, and the remainder had
unchanged HE severity at time of LT (Table 3).

Liver Transplantation Wait-List Mortality

Overall 90-day mortality among LT wait-list patients
was 6.3%. However, patients with grade 3-4 HE at
time of wait-list registration had significantly higher
90-day wait-list mortality compared with patients
with grade 1-2 HE or patients with no HE (24.4% versus 6.8% versus 3.5%; P < 0.001; Fig. 1). This impact
of HE on 90-day wait-list mortality was similar
between men and women. Similar trends were seen
when evaluating 30-day and 60-day wait-list mortality

LIVER TRANSPLANTATION, Vol. 20, No. 12, 2014

WONG, GISH, AND AHMED 1457

TABLE 3. Change in Severity of HE From Time of Wait-List Registration to Time of Transplantation

Among LT Recipients
Wait-List Registration
HE severity
No HE
Grade 1-2
Grade 3-4

Increased

Decreased

Unchanged

Percentage

Percentage

Percentage

Percentage

34.7
58.3
7.0

14,407
24,178
2898

32.1
8.9

4627
2157

11.2
35.9

2707
1041

67.9
79.9
64.1

9780
19,314
1,857

Figure 1.

Overall 30-day, 60-day, and 90-day survival among patients awaiting LT.

(Fig. 1). On multivariate Cox proportional hazards

modeling of 90-day wait-list mortality, patients with
grade 3-4 HE had significantly greater risk of death
compared with patients with no HE at time of wait-list
registration (hazard ratio [HR] 5 1.65, 95% CI 5 1.441.89; P < 0.001; Fig. 2). Compared with women, men
had lower risk of death (HR 5 0.91, 95% CI 5 0.850.99; P 5 0.03). Compared with non-Hispanic whites,
Hispanics had a significantly lower risk of wait-list
mortality (HR 5 0.88, 95% CI 5 0.80-0.98; P 5 0.02),
but no significant difference in mortality was seen
among blacks or Asians (Fig. 2). HCV diagnosis, compared with non-HCV, was not associated with a significant difference in 90-day wait-list mortality
(HR 5 1.03, 95% CI 5 0.95-1.11; P 5 0.45).
Although our multivariate regression analysis demonstrated a 66% increased risk of 90-day wait-list mortality among patients with grade 3-4 HE compared with
patients with no HE at time of wait-list registration, we
hypothesized that the degree of increased risk was not
uniform across the MELD score spectrum. To test this
hypothesis, 90-day wait-list survival was stratified by
both degree of HE (no HE versus grade 1-2 HE versus

grade 3-4 HE) and MELD score at time of wait-list

registration (Fig. 3). A line of best fit was determined by
using polynomial modeling, and a second-order polynomial (quadratic) demonstrated the most accurate statistical fit. The resulting smooth curve depicts the
relationship between 90-day wait-list survival and
MELD score at time of wait-list registration stratified by
severity of HE (Fig. 3). Overall, 90-day survival was significantly different among the three curves, with significantly lower 90-day wait-list survival among patients
with grade 3-4 HE. However, the survival difference
was not uniform across MELD scores, and a greater
survival difference was seen with higher MELD scores
(Fig. 3). For example, among patients with MELD score
of 20 at time of wait-list registration, those with grade
3-4 HE had a 90-day wait-list survival of 84.8% compared with 93.3% among patients with no HE. Among
patients with MELD score of 30 at time of wait-list
registration, 90-day wait-list survival was 61.1% among
those with grade 3-4 HE compared with 78.1% among
those with no HE (Fig. 3).
Using regression methods, we calculated the
AUROC for predicting 90-day wait-list survival

1458 WONG, GISH, AND AHMED

Figure 2.

LIVER TRANSPLANTATION, December 2014

Multivariate Cox proportional hazards model of 90-day probability of death among patients on the LT wait list.

associated with MELD score alone and MELD score

with inclusion of HE severity (Fig. 4). By MELD score
alone, the AUROC for predicting 90-day wait-list survival was 0.6508, and when HE severity was included
the AUROC improved to 0.6863 (Fig. 4). To evaluate
further the impact of including HE severity with
MELD score on improved reclassification of 90-day
wait-list survival, additional analyses were performed
to determine the overall 90-day wait-list survival with
and without HE stratification. This was further substratified by MELD score to determine the more specific impact of HE inclusion at each MELD score
(Supporting Information Table A).

DISCUSSION
Chronic liver disease is one of the leading causes of
morbidity and mortality in the United States.1 Although
LT offers a curative option for patients with end-stage
liver disease, the numbers of patients awaiting LT far
outweigh the availability of organs to be allocated for
LT.5-7 The MELD score has been used to prioritize
patients on the LT wait list. However, HE is currently
not factored into the prioritization for LT.8,9 Our current
study evaluated the impact of HE at the time of waitlist registration on 90-day wait-list mortality. Patients
with grade 3-4 HE had 66% higher risk of 90-day waitlist mortality compared with patients without HE.

LIVER TRANSPLANTATION, Vol. 20, No. 12, 2014

Figure 3.
of HE.

Overall 90-day wait-list survival stratified by degree

Since the introduction of the MELD score in 2003

as an objective measure for prioritizing patients with
end-stage liver disease for LT, several studies have

Figure 4. Receiver operating curve analysis of MELD alone versus MELD with HE severity at predicting 90-day LT wait-list
survival.

WONG, GISH, AND AHMED 1459

attempted to improve upon its performance in predicting wait-list mortality. In the original multivariate
model used to establish the MELD score for the prioritization of LT, the addition of HE was not shown to
impact the c-statistic of the MELD model significantly.9 However, other studies prior to the implementation of the MELD score did demonstrate a
significantly increased mortality associated with
HE.19,20 Subsequent authors have reported similar
findings, raising concern that the lack of considering
HE in prioritization of patients for LT may significantly underestimate liver disease severity and mortality risk among patients with HE.14-18 An early
study by Yoo et al.14 evaluated 66 patients undergoing
LT evaluation to determine the correlation of MELD
score with severity of HE. HE was assessed based on
electroencephalogram and a series of 6 neuropsychiatric tests, including Trail Making Tests A and B, ReyOsterreith Complex Figure Test including Reycopy
and Reyrecall, Hopkins Verbal Learning Test, and
Mini-Mental State Examination. The study indicated
no significant difference in MELD scores across severity of HE and demonstrated poor correlation of MELD
score with severity of HE, raising concern that
patients with severe HE are disadvantaged in the current MELD model and may not receive LT in a timely
manner.14 Said et al.18 evaluated 1611 consecutive
patients with chronic liver disease seen at a single
university hospital health care system. Their analyses
demonstrated that HE was a strong and significant
predictor of mortality among patients with chronic
liver disease and that the addition of HE to the MELD
score would improve its prognostic value. However,
the inherent subjectivity of grading HE severity, compounded by effect of patient-specific factors (eg, medication noncompliance), continued to raise concerns
about the incorporation of HE into current LT prioritization discussions. Stewart et al.15 performed a retrospective evaluation of 494 patients with cirrhosis that
included 223 patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) placement and
271 patients hospitalized for decompensated cirrhosis. On univariate analyses, grade >3 HE was associated with significantly increased risk of mortality
(HR 5 3.68; 95% CI 5 1.85-7.3; P < 0.001) among
patients undergoing TIPS, and grade >2 HE was associated with significantly increased mortality among
hospitalized patients. Furthermore, when HE and
MELD were considered together, HE remained
strongly predictive of mortality among hospitalized
patients, demonstrating that HE may provide additional prognostic information independent of MELD
score.15 Another important factor to consider is the
evolution of and improvement in diagnosis and treatment of HE over time; better recognition and treatment of HE in the latter part of the study may lead to
less significant impact of grade 3-4 HE on 90-day
wait-list survival. We performed a subanalysis separating our cohort into two periods, 2003-2007 and
2008-2012. Although patients with grade 3-4 HE
continued to demonstrate significantly lower 90-day

1460 WONG, GISH, AND AHMED

wait-list survival compared with patients with no HE

in both the earlier and the later periods, patients with
grade 3-4 HE in the later period (2008-2012) did in
fact have improved survival compared with patients
with grade 3-4 HE in the earlier period (2003-2007;
80.7% versus 69.8%; P<0.01). Our current study
uses 10 years of UNOS registry data that includes all
adult LT registrants in the United States We demonstrate that patients with grade 3-4 HE at time of waitlist registration have 66% increased risk of 90-day
wait-list mortality independent of MELD score. Furthermore, MELD score does not accurately predict 90day wait-list mortality among patients with grade 3-4
HE, such that these patients have 90-day mortality
rates significantly higher than nonencephalopathic
patients with similar MELD scores (Fig. 3). The incorporation of HE into the discussion regarding LT priority not only will improve prognostication but will help
in prioritizing the sickest patients for LT.
The impact of HE on survival among patients with
cirrhosis is well established.2-4,17,21 It is a marker of
decompensated disease and is a component of the
Child-Pugh-Turcotte scoring system.22 However, concerns have been raised over the potential subjectivity
that affects the grading of HE severity, and this subjectivity might have influenced its exclusion from the
original MELD scoring model. Although there are
several scoring systems for grading severity of HE,
the West Haven Criteria are commonly used.23-25
Ham et al.16 recently proposed the standardization of
the West Haven Criteria for the assessment of HE
among patients with chronic liver disease. Other
objective tools for assessing for HE include the psychometric hepatic encephalopathy score and the critical flicker frequency.25-27 Although the West Haven
Criteria are the most commonly used tool for assessing HE severity, they too are susceptible to some
degree of subjectivity and intraobserver variability.
Although no studies have clearly made a detailed
assessment of intraobserver variability when using
the West Haven Criteria, it is conceivable that variability exists in accurately identifying different
grades of HE severity, especially distinguishing grade
1 from grade 2 HE. Thus, although the importance of
implementing a single scoring system will help
improve consistency of HE assessment across patient
populations and practice environments, it is even
more important to develop a more objective tool that
will improve accuracy and reproducibility of HE
severity assessment and thereby lead to a tool that
harbors greater clinical significance and greater
prognostic ability. Prospective studies are needed to
pilot the incorporation of such a tool into the MELD
score to assess liver transplant wait-list mortality
more accurately.
The strengths of the current study include the
inclusion of 10 years of population-based data inclusive of all adult liver transplant registrants in the
United States. The large cohort from a single registry
source allows for consistency of data reporting, and
improves the generalizability of the study findings.

LIVER TRANSPLANTATION, December 2014

However, the utilization of registry data has several

limitations. The available data are subject to coding
and data entry errors that are inherent in databasebased studies. Specifically, the coding of HE severity
may not follow uniform reporting measures and is
not necessarily subject to cross-checking for accuracy. Furthermore, it is not clear whether all reporting centers used similar systems for grading HE
severity. The grading of HE severity has been
criticized for its potential for subjective bias, and this
might have influenced its exclusion from the original
MELD score and the gravitation away from ChildPugh score to MELD for LT allocation. This limitation
is even greater in a retrospective assessment. Furthermore, data regarding treatment for HE and how
well patients responded to therapy were not available
for inclusion in the study. In addition, disparities in
access to HE treatment might also have impacted the
severity of HE at time of listing as well as progression
of HE while on the LT wait list, but surrogate
markers of disparities in medication access were not
available in the registry. It is also well known that
severity of HE is a dynamic process, and, with progression of disease or initiation of treatment, severity
of HE may change over time. Although the current
database does not provide severity of HE at several
time points, our findings are still clinically applicable,
such that reassessment of HE along with MELD score
among wait-list patients can be used to provide an
updated estimate of 90-day wait-list mortality. This
concept of reassessing a patients clinical situation to
provide an updated assessment of prognosis is similar to the current model used with MELD scores.
However, it is likely not the HE itself that is directly
causative of increased mortality; rather, it is a marker
for more severe liver disease and risk of death that
are not completely captured by MELD alone. The
UNOS region where the patient was listed for LT may
be an additional potentially confounding variable.
Disparate average MELD scores at time of LT lead to
disparate length of time waiting for LT in different
UNOS regions, and this may impact the effect of HE
severity of 90-day wait-list survival. We performed a
subanalysis to reassess the impact of HE severity of
90-day wait-list survival stratified by UNOS region.
Although some variation was seen in the magnitude
of impact of HE severity on 90-day survival in different UNOS regions, the significantly lower 90-day
wait-list survival among patients with grade 3-4 HE
compared with patients with no clinical evidence of
HE was consistent across all regions. Nevertheless,
our large cohort study demonstrates a significant
association between HE and 90-day wait-list
mortality.
In conclusion, the results of the current study demonstrate that greater severity of HE at time of LT waitlist registration significantly increases 90-day wait-list
mortality independent of MELD score. Incorporating
HE in the decision regarding LT wait-list priority will
improve prognostication and thereby improve the prioritization of patients awaiting LT.

LIVER TRANSPLANTATION, Vol. 20, No. 12, 2014

WONG, GISH, AND AHMED 1461

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