LIVER TRANSPLANTATION 21:873–880, 2015

ORIGINAL ARTICLE

The Impact of Pretransplant Hepatic

Encephalopathy on Survival Following Liver
Transplantation
Robert J. Wong,1 Maria Aguilar,2 Robert G. Gish,3,4 Ramsey Cheung,4,5 and Aijaz Ahmed4
1
Division of Gastroenterology and Hepatology, and 2Department of Medicine, Alameda Health System,
Highland Hospital, Oakland, CA; 3Hepatitis B Foundation, Doylestown, PA; 4Division of Gastroenterology
and Hepatology, Stanford University School of Medicine, Stanford, CA; and 5Division of Gastroenterology
and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA

Hepatic encephalopathy (HE) is a surrogate marker of liver disease severity, and more severe HE is associated with higher
mortality among patients with chronic liver disease. However, whether severity of HE at the time of liver transplantation (LT)
directly impacts post-LT survival or whether this suspected mortality linkage is due to more severe liver disease and subse-
quently higher rates of post-LT infection is not well defined. Using population-based data from the 2003 to 2013 United Net-
work for Organ Sharing registry, we evaluated the impact of HE at the time of LT on post-LT survival among adults in the
United States. Survival was stratified by HE severity (none, grade 1-2, grade 3-4) and Model for End-Stage Liver Disease
score and was evaluated using Kaplan-Meier methods and multivariate Cox proportional hazards models. From 2003 to
2013, 59,937 patients underwent LT (36.1%, no HE; 53.8%, grade 1-2 HE; 10.2%, grade 3-4 HE). Compared to no HE,
patients with grade 3-4 HE had significantly lower overall post-LT survival (1-year, 82.5% versus 90.3%; P < 0.001; 5-year,
69.1% versus 74.4%; P < 0.001). On multivariate regression, grade 3-4 HE was independently associated with lower overall
post-LT survival (HR, 1.27; 95% CI, 1.17-1.39; P < 0.001). However, the increased mortality associated with HE is observed
primarily within the first year following LT and was a reflection of higher rates of infection-related deaths among patients with
more severe HE. In conclusion, grade 3-4 HE at the time of LT is associated with lower post-LT survival, with a proposed
direct or indirect association of more severe HE before LT with increased rates of post-LT infections. Increased awareness
and vigilance toward treating HE before LT and more aggressive monitoring and treatment for infections in the perioperative
setting may improve LT outcomes. Liver Transpl 21:873-880, 2015. V C 2015 AASLD.

Received February 26, 2015; accepted April 13, 2015.

The implementation of the Model for End-Stage Liver patients with the highest MELD score and thereby
Disease (MELD) score in the prioritization of patients the sickest patients first.1,2 Although the MELD score
awaiting liver transplantation (LT) is based on the performs well in predicting the risk of wait-list mor-
principle of using objective criteria to offer LT to tality, it does not incorporate the severity of hepatic

Additional supporting information may be found in the online version of this article.

Abbreviations: BMI, body mass index; CI, confidence interval; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HE, hepatic
encephalopathy; HR, hazard ratio; INR, international normalized ratio; IRB, institutional review board; LT, liver transplantation;
MELD, Model for End-Stage Liver Disease; OPTN, Organ Procurement and Transplantation Network; SD, standard deviation;
UNOS, United Network for Organ Sharing.

Financial support: Nothing to report.

Potential conflict of interest: Nothing to report.

Address reprint requests to Robert J. Wong, M.D., M.S., Division of Gastroenterology and Hepatology, Alameda Health System - Highland Hospital,
1411 East 31st Street, Highland Care Pavilion - 5th Floor Endoscopy Unit, Oakland, CA 94602. Telephone: 510-437-6531; FAX: 510-437-6532;
E-mail: rowong@alamedahealthsystem.org

DOI 10.1002/lt.24153
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 2015 American Association for the Study of Liver Diseases.

V
874 WONG ET AL.
encephalopathy (HE) into risk calculations because of
the lack of an objective and quantitative scoring sys-
tem. The grading systems for HE have significant
limitations, and the degree of subjectivity with cur-
rent systems have called into question the accuracy
of incorporating HE into risk calculations.3-6 How-
ever, the impact of HE on survival among patients
with cirrhosis is well established, and HE severity is
a component of the well-validated Child-Turcotte-
Pugh scoring system.7-10 Despite these limitations, a
recent study using data from the United Network for
Organ Sharing (UNOS) LT registry in the United
States demonstrated that patients with grade 3-4 HE
had significantly higher wait-list mortality when com-
pared to patients with no HE, independent of MELD
score.3
However, once a patient undergoes LT, it is not
clear if the severity of HE at the time of LT affects the
post-LT outcomes. A recent retrospective cohort study
of 393 adult LT recipients evaluated the impact of
pre-LT severe HE on post-LT outcomes.11 Although
there was a nonsignificant trend toward a lower 1-
year survival among patients with severe HE com-
pared to patients without severe HE (HR, 2.19; P 5
0.08), overall hospital length of stay was significantly
longer in patients with severe HE. Furthermore, per-
sistent encephalopathy and cognitive impairments
may persist following LT among patients with pre-LT
HE, which may increase the risk for infections related
to aspiration events.12-18 Currently, residual HE or
cognitive impairments following LT are not well cap-
tured by LT registries. Understanding the impact of
pre-LT HE on post-LT outcomes is important in rais-
ing awareness of the need to aggressively treat HE
during the preoperative period. Using US population–
based data from the UNOS and Organ Procurement
and Transplant Network (OPTN), the current study
evaluates the impact of pre-LT HE on survival follow-
ing LT.
PATIENTS AND METHODS
Study Population
Using data from the UNOS/OPTN registry, we eval-
uated adult men and women (age > 18 years) with
chronic liver disease who underwent LT in the United
States from January 1, 2003 to December 31, 2013.
Patients undergoing LT for fulminant liver failure via
status 1A prioritization were excluded. MELD scores at
the time of LT were calculated for each individual using
a standard formula that incorporates the natural loga-
rithms of the international normalized ratio (INR) of
prothrombin time, bilirubin, and creatinine with a
lower limit of 1 mg/dL for all variables and an upper
limit of 4 mg/dL for creatinine. Patients on hemodialy-
sis were given a creatinine score of 4 mg/dL.
HE severity at the time of LT was graded using the
West Haven Criteria (grade 0, no HE; grade 1, trivial
lack of awareness, euphoria or anxiety, shortened
attention span, impaired performance of addition or
LIVER TRANSPLANTATION, July 2015
subtraction; grade 2, lethargy or apathy, minimal dis-
orientation for time or place, subtle personality
change, inappropriate behavior; grade 3, somnolence
to semistupor but responsive to verbal stimuli, confu-
sion, gross disorientation; grade 4, coma [unrespon-
sive to verbal or noxious stimuli]).4,6 The grade of HE
at the time of LT (no HE, grade 1-2 HE, grade 3-4 HE)
was based on clinical diagnosis coding as documented
in UNOS. Data regarding the treatment for HE was
not captured in the UNOS registry, and additional
data points assessing the presence and severity of HE
following LT were not available for analysis. Survival
following LT was our primary outcome, and the etiol-
ogy of post-LT death as provided by UNOS was
included in our analyses.
Statistical Analysis
Descriptive statistics were stratified by severity of HE
and presented as proportions (%) and frequencies (n)
for categorical variables, mean and standard devia-
tion (SD) for normally distributed continuous varia-
bles, and median and range for nonnormally
distributed variables. Comparisons between groups
were performed with chi-square testing and analysis
of variance methods. Survival following LT was eval-
uated using Kaplan-Meier methods and log-rank test-
ing for equality of survivor functions. Post-LT survival
was further stratified by MELD score and severity of
HE to determine whether the association of HE and
post-LT survival is dependent on MELD score at the
time of LT. Specifically, we calculated 1-year and 5-
year post-LT survival rates for each MELD score
(from 6 to 40) for patients with no HE, grade 1-2 HE,
and grade 3-4 HE. Using this stratified approach, lin-
ear regression models were applied to determine
whether a significant association between HE at the
time of LT and post-LT survival was present, inde-
pendent of MELD score at LT. Overall long-term sur-
vival following LT was further evaluated using
multivariate Cox proportional hazards models. For-
ward stepwise regression methods included variables
that were biologically significant (eg, age, sex) and
those that demonstrated significant associations in
the univariate models (P < 0.10). The final multivari-
ate model was adjusted for sex, age at the time of LT,
hepatitis C virus (HCV) infection (versus non-HCV),
hepatocellular carcinoma (HCC; versus non-HCC),
diabetes, ascites, race/ethnicity, MELD score at the
time of LT, and HE grade. Statistical significance was
met with a 2-tailed P value < 0.05. Differences in
cause of death following LT were stratified by HE
grade at the time of LT and evaluated using chi-
square testing and probability density functions. All
statistical analyses were performed using the Stata
statistical package, version 10 (Stata Corporation,
College Station, TX) and Prism Statistical Software,
version 6.0 (GraphPad Software, Inc., La Jolla, CA).
This study was exempt from institutional review
board (IRB) review after Stanford University Medical
Center IRB review.
LIVER TRANSPLANTATION, Vol. 21, No. 7, 2015 WONG ET AL. 875

TABLE 1. Characteristics of LT Patients Stratified by Severity of HE at the Time of LT

No HE, Grade 1-2 HE, Grade 3-4 HE,

n 5 21,625 n 5 32,226 n 5 6086 P Value
Sex, male 14,776 (68.3) 21,959 (68.1) 3928 (64.5) <0.001
Age, years 53.7 6 10.9 54.2 6 9.3 52.7 6 10.3 <0.001
Race/ethnicity <0.001
Non-Hispanic white 15,215 (71.0) 23,850 (74.8) 4363 (72.6)
Black 2295 (10.7) 2710 (8.5) 553 (9.2)
Hispanic 2541 (11.9) 4354 (13.7) 862 (14.4)
Asian 1391 (6.5) 978 (3.1) 229 (3.8)
HCV 8199 (51.4) 13,392 (49.1) 2215 (46.6) <0.001
HCC 6521 (30.2) 3960 (12.3) 333 (5.5) <0.001
MELD score 17.2 6 8.7 22.3 6 9.0 29.9 6 8.7 <0.001
Moderate ascites 2725 (12.9) 10,036 (31.2) 4155 (68.3) <0.001
Diabetes 3941 (19.5) 5948 (20.1) 1070 (19.2) 0.13
Obesity, BMI > 30 kg/m2 6411 (29.7) 11,385 (35.3) 2086 (34.3) <0.001
BMI, kg/m2 27.6 6 5.5 28.4 6 5.7 28.1 6 5.9 <0.01
Albumin g/dL 3.1 6 0.7 2.9 6 0.7 2.9 6 0.8 0.02
Sodium mmol/L 136.8 6 4.6 135.4 6 5.2 137.2 6 6.4 0.02
INR 1.4 (0.9-4.3) 1.7 (1.0-5.2) 2.2 (1.1-9.9) <0.001

NOTE: Data are given as n (%), as mean 6 SD, or as median (range).

RESULTS 5-year post-LT survival (69.1% [grade 3-4 HE] versus

Overview
From 2003 to 2013, 59,937 patients with chronic liver
disease underwent LT, among which 10.2% (n 5 6086)
had grade 3-4 HE, 53.8% (n 5 32,226) had grade 1-2
HE, and 36.1% (n 5 21,625) had no HE at the time of
LT (Table 1). Although the majority of patients were
men, there was a higher proportion of men with no
HE compared to patients with grade 3-4 HE (68.3%
versus 64.5%; P < 0.001). When compared to patients
with no HE at the time of LT, there was a higher pro-
portion of Hispanics (14.4% versus 11.9%; P < 0.001)
and lower proportion of Asians (3.8% versus 6.5%;
P < 0.001) among patients with grade 3-4 HE (Table
1). When we evaluated the proportion of patients with
grade 3-4 HE within each race/ethnic group, 100% of
non-Hispanic whites, 9.9% of blacks, 11.0% of His-
panics, and 8.8% of Asians had grade 3-4 HE. LT
recipients with no HE were also significantly more
likely to have concurrent HCC when compared to
patients with grade 3-4 HE (30.2% versus 5.5%;
P < 0.001). Patients with grade 3-4 HE had higher
MELD scores and higher prevalence of concurrent
moderate ascites (Table 1).
Survival Following LT
Compared to patients with no HE at the time of LT,
patients with grade 3-4 HE had significantly lower
survival following LT (Fig. 1). For example, overall 1-
year post-LT survival among patients with grade 3-4
HE was 82.5% (95% CI, 81.6%-83.4%) compared to
90.3% (95% CI, 89.8%-90.7%) among patients with
no HE. Similar trends were seen when evaluating
74.4% [no HE]); P < 0.001; Fig. 1). To determine
whether the impact of HE on post-LT survival varied
by MELD score at the time of LT, we stratified post-LT
survival by MELD score categories (<15, 15-25, >25;
Fig. 2). Among patients with a MELD score of <15,
there was a nonsignificant trend toward lower 1-year
post-LT survival among patients with grade 3-4 HE
compared to patients with no HE at the time of LT.
With higher MELD scores, the impact of HE on post-
LT survival became more significant. For example,
among patients with a MELD score of >25 at the time
of LT, patients with grade 3-4 HE had significantly
lower 1-year post-LT survival when compared to
patients with no HE at the time of LT (79.2% versus
85.9%; P < 0.01; Fig. 2). Similar trends were seen
when evaluating 5-year post-LT survival with the
greatest impact of HE seen among patients with a
MELD score of >25 (64.6% versus 71.5%; P < 0.01;
Fig. 2). Using linear regression methods, we further
evaluated the impact of HE stratified by incremental
1-unit increases in MELD score at the time of LT (Fig.
3). Although higher MELD scores were associated
with lower 1-year post-LT survival for all categories of
HE (grade 3-4 HE, P < 0.001; grade 1-2 HE, P < 0.02;
no HE, P < 0.001), there was no significant difference
in 1-year post-LT survival between patients with grade
3-4 HE versus no HE when stratified by individual
MELD score at the time of LT (P 5 0.18; Fig. 3). Simi-
lar findings were observed for 5-year survival, with no
significant difference in survival between grade 3-4
HE versus no HE when stratified by individual MELD
score at the time of LT (P 5 0.47; Fig. 3).
However, when MELD at the time of LT was
adjusted for in the multivariate Cox regression model,
876 WONG ET AL.
Figure 1. Overall post-LT survival stratified by severity of HE at the time of LT.
grade 3-4 HE at the time of LT was independently
associated with significantly lower post-LT survival
compared to patients with no HE (HR, 1.27; 95% CI,
1.17-1.39; P < 0.001; Table 2). Compared to non-
Hispanic whites, blacks had lower post-LT survival,
whereas Asians and Hispanics had higher post-LT
survival. HCV, HCC, and concurrent diabetes mellitus
were also associated with significantly lower survival
following LT (Table 2). Given that both HCV and HCC
are associated with lower overall post-LT survival, we
performed a sensitivity analysis by removing each of
these groups to determine whether the impact of HE
on post-LT survival persisted. Despite removing HCV
and HCC patients, the effect measure associated with
the impact of HE on survival following LT remained
unchanged.
To further investigate these discrepant results, we
evaluated the etiology of post-LT death stratified by
grade of HE at the time of LT (Supporting Table 1). In
addition, the etiology of post-LT death was also eval-
uated separately for patients who died within 1 year
following LT and patients who survived 1 year but
died within 5 years following LT, given the hypothesis
that the increased mortality associated with HE may
be primarily observed within the first year following
LT. Overall, infection was a leading etiology of post-LT
death, accounting for 18.4% of deaths among patients
with grade 3-4 HE, 15.4% among patients with grade
1-2 HE, and 14.4% among patients with no HE (Sup-
porting Table 1). Among patients who died within 1
year following LT, higher rates of infection-related
deaths were seen with higher grades of HE, but this
trend was not seen among patients who survived
beyond 1 year but died within 2 to 5 years. Using
probability density functions, patients with grade 3-4
HE demonstrated a significantly different 1-year prob-
ability death curve compared to patients with grade 1-
2 HE or patients with no HE, but no difference was
LIVER TRANSPLANTATION, July 2015
seen in 5-year probability death curves (Fig. 3). A
major contributor of HE grade-specific differences in
1-year probability death curves was a result of differ-
ences in rates of infection-related deaths at 1 year
between patients with different severities of HE (Fig.
4). We also evaluated hospital stay following LT strati-
fied by HE severity (no HE, median, 9 days, range, 2-
739; grade 1-2 HE, median, 10 days, range, 1-1121;
grade 3-4 HE, median, 16 days, range, 1-419).
DISCUSSION
Current prioritization models among patients with
chronic liver disease awaiting LT do not incorporate
HE severity. Although previous studies have sug-
gested that severity of HE is associated with higher LT
wait-list mortality, this observation may be explained
by the fact that HE is a surrogate for more severe
overall liver dysfunction, thereby leading to higher
wait-list mortality.2,3,11,18-20 It follows then that if
more severe HE is a surrogate for more severe liver
dysfunction before LT, more severe HE at the time of
LT may be associated with higher perioperative com-
plications leading to higher postoperative mortality
because of increased risks of post-LT infections. The
impact of pre-LT HE on post-LT outcomes is not well
understood, and current studies are conflicting as to
whether inadequately treated HE at the time of LT
negatively impacts post-LT survival and if correcting
HT pre-LT would improve post-LT survival and cogni-
tive function.11,13,18-22 Using MELD-era registry data
from UNOS/OPTN, our current study suggests that
although patients with grade 3-4 HE at the time of LT
had 28% higher risk of post-LT mortality compared to
patients with no HE, this survival difference is pre-
dominantly explained by differences in survival within
the first year following LT. Furthermore, the higher
LIVER TRANSPLANTATION, Vol. 21, No. 7, 2015
Figure 2. Overall 1-year and 5-year survival following LT stratified by MELD categories. Error bar represents upper limit of 95% confi-
dence interval.
post-LT mortality associated with grade 3-4 HE is
largely explained by infection-related deaths.
The higher post-LT mortality associated with severe
HE is not entirely clear and reflects the multifactorial
nature of post-LT death. In a single-center retrospec-
tive cohort study of 393 adult LT recipients in the
United States from 2002 to 2005, Brandman et al.11
evaluated the impact of severe HE within 30 days
before LT on post-LT outcomes. Patients with severe
HE had a significantly longer hospital stay, greater
odds of infection in the post-LT period (odds ratio,
3.26; 95% CI, 1.61-6.59), and greater odds of pro-
longed post-LT altered mental status (odds ratio,
3.62; 95% CI, 1.80-7.29). However, the study noted
no significant differences in post-LT survival or etiol-
ogy of post-LT death between patients with severe HE
and those with no HE. The relationship between HE
and post-LT mortality was further diminished after
adjusting for MELD score, and HE alone was not an
independent predictor of post-LT mortality.11 How-
ever, the authors acknowledged their relatively
smaller sample size and limited power to detect
statistically significant differences in post-LT survival
between groups with and without severe HE. In
addition, the overall post-LT survival among all
WONG ET AL. 877
patients was higher than expected, which may have
further limited the ability to detect survival differen-
ces.11 In our current study, whereas there was no sig-
nificant difference in 1-year post-LT survival between
patients with grade 3-4 HE versus no HE when strati-
fied by individual MELD scores, after correction for
MELD score in a multivariate Cox proportional haz-
ards model, the presence of grade 3-4 HE was inde-
pendently associated with lower post-LT survival
compared to patients with no HE.
The impact of HE on post-LT survival is complex
and likely reflects multiple measured and unmeas-
ured factors. Although more severe HE at the time of
LT may simply reflect more severe liver dysfunction,
which is associated with a higher risk of perioperative
complications and mortality, additional studies have
also demonstrated that more severe HE is associated
with higher rates of post-LT infections, which may
subsequently directly or indirectly impact post-LT
outcomes.2,3,11,13,18,20,22-25 Our current study demon-
strated that grade 3-4 HE is associated with increased
post-LT mortality, but this increase in mortality was
primarily seen within the first year following LT.
When evaluating the cause of death following LT, we
also observed that the increased mortality associated
878 WONG ET AL. LIVER TRANSPLANTATION, July 2015

with some caution. The observational nature of our

Figure 3. Crude 1-year and 5-year post-LT survival stratified by
HE grade and MELD score.
with HE is significantly associated with infection-
related deaths. Although these findings confirm the
findings of previous studies, they must be interpreted
study and others only allows for the determination of
association and not causation. Thus, although we
postulate that more severe HE at the time of LT may
lead to more infections following LT, it is also plausi-
ble that post-LT de novo infections precipitate the
development of HE following LT, a biological mecha-
nism that is well established and may further contrib-
ute to poorer survival.6,22,26-28 Nevertheless, our
study does raise concerns that severe HE before LT is
directly or indirectly associated with higher post-LT
mortality, and there is a need for increased awareness
and vigilance to aggressively treat pre-LT HE and peri-
operative infections.
The current study incorporates 11 years of MELD
era data from a population-based LT registry that
includes all adult LTs performed in the United States.
The utilization of data from a single registry strength-
ens the consistency of demographic and clinical data
reported, and the use of population-based data
improves the generalizability of our findings. However,
there are inherent limitations of registry-based cohort
studies that must be acknowledged. Data available for
study analyses are subject to potential data entry
errors or miscoding, and cross-checking for accuracy
of data entry may not be implemented in all reporting
centers. Specific to our study, although data regard-
ing HE severity are reported from grades 0 to 4 as per
West Haven Criteria, it is not entirely clear whether all
reporting centers used structured grading schemes,
and there exists the potential for misclassification of
HE severity both at the time of diagnosis and at the
time of data entry. The relative subjectivity of HE

TABLE 2. Cox Proportional Hazards Model Evaluating Overall Survival Following LT

Univariate Multivariate

HR 95% CI P Value HR 95% CI P Value

HE Grade
No NE 1.00 Reference — 1.00 Reference —
Grade 1-2 HE 1.06 1.02-1.10 <0.01 1.04 0.98-1.11 0.15
Grade 3-4 HE 1.34 1.27-1.41 <0.001 1.27 1.17-1.39 <0.001
MELD score 1.01 1.01-1.01 <0.001 1.01 1.01-1.02 <0.001
Race/ethnicity
Non-Hispanic white 1.00 Reference — 1.00 Reference —
Black 1.32 1.26-1.39 <0.001 1.30 1.32-1.40 <0.001
Hispanic 0.95 0.91-1.00 0.07 0.88 0.82-0.94 <0.001
Asian 0.78 0.72-0.85 <0.001 0.86 0.75-0.97 0.02
Sex 1.04 1.01-1.08 0.01 0.98 0.93-1.03 0.44
Recipient age 1.02 1.01-1.02 <0.001 1.02 1.02-1.02 <0.001
HCV 1.42 1.36-1.47 <0.001 1.55 1.48-1.63 <0.001
HCC 1.17 1.12-1.22 <0.001 1.20 1.13-1.28 <0.001
Year of LT 0.99 0.99-1.00 <0.01 0.98 0.97-0.99 <0.001
Diabetes mellitus 1.28 1.23-1.34 <0.001 1.23 1.17-1.30 <0.001
Ascites 1.09 1.04-1.13 <0.001 0.99 0.92-1.06 0.76
Serum sodium 1.01 1.01-1.01 <0.001 1.01 1.00-1.01 <0.01
Portal vein thrombosis 1.26 1.18-1.34 <0.001 1.23 1.13-1.33 <0.001
Dialysis 1.52 1.45-1.60 <0.001 1.35 1.25-1.46 <0.001
UNOS region 0.99 0.99-1.00 0.70 1.01 1.00-1.01 0.08
Donor age 1.01 1.01-1.01 <0.001 1.01 1.01-1.01 <0.001
LIVER TRANSPLANTATION, Vol. 21, No. 7, 2015
Figure 4. Probability density function of post-LT death stratified by HE severity.
severity has also been criticized, and this may further
contribute to misclassification of HE in our study.
Although severity of HE at the time of LT was avail-
able for analysis, data regarding HE treatment and
post-LT HE severity were not available. It is possible
that differences in how aggressive HE was treated
after LT may have impacted perioperative complica-
tions (eg, aspiration, infection). Furthermore, evaluat-
ing the severity of HE at the time of LT does not
capture the period immediately preceding LT, and
patients who had severe HE in the short-term before
LT may not be captured in the current analysis. How-
ever, it is likely that HE at the time of LT is not
directly causative of increased post-LT mortality but
rather a surrogate for other unmeasured factors (eg,
sepsis, multiorgan failure) that impact post-LT out-
comes. In an attempt to clarify this association, our
study demonstrated that the higher mortality seen
among patients with grade 3-4 HE during the first
year following LT is partly explained by higher
infection-related deaths. However, more specific
details about the source and severity of the infection
(eg, what organ system involved, what organism iso-
lated, what treatments attempted) were not available
for analysis. Furthermore, data for etiology of death
following LT is provided in broad categories, and more
specific details (eg, what types of perioperative compli-
cations, what types of malignancies, what types of
cardiovascular complications) were not available for
inclusion in this study. In addition, other clinical and
nonclinical data (eg, socioeconomic status) including
unmeasured confounders that were not available for
analyses may have affected overall post-LT survival.
Although our data was inclusive of all adult LTs
in the United States, we did not have the ability to
evaluate outcomes at the level of each individual LT
center, and differences in practice patterns at the
WONG ET AL. 879
center level may contribute to some of the variations
in post-LT outcomes observed. Despite these limita-
tions, our large population-based cohort study adds
greatly to better understanding the potential impact of
pre-LT HE on post-LT outcomes.
In conclusion, among adult patients with chronic
liver disease in the United States, the presence of
grade 3-4 HE at the time of LT was independently
associated with lower survival following LT. This
increased mortality associated with severe HE is
observed primarily within the first year following LT
and is a reflection of higher rates of infection-related
deaths among patients with more severe HE.
Increased awareness and vigilance toward treating HE
in the pre-LT setting as well as infections in both the
pre-LT and post-LT settings may further contribute to
improved outcomes among patients with chronic liver
disease in the United States.
ACKNOWLEDGMENT
We would like to acknowledge the statistical assis-
tance provided by Dr. Jerry Gardner.
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