International Journal of Clinical Medicine, 2012, 3, 125-131
http://dx.doi.org/10.4236/ijcm.2012.32025 Published Online March 2012 (http://www.SciRP.org/journal/ijcm)
125
Effects of Illness Severity and Alcohol Use on Cognition in
End Stage Liver Disease after Controlling for General
Intelligence and Mood
——Cognition in End Stage Liver Disease
Robert P. Hart1*, Douglas P. Gibson1, Melanie K. Bean2, Robert A. Fisher3
1Department of Psychiatry, Virginia Commonwealth University, Richmond, USA; 2Departments of Pediatrics and Psychology, Vir-
ginia Commonwealth University, Richmond, USA; 3Department of Surgery, Virginia Commonwealth University, Richmond, USA.
Received December 4th, 2011; revised January 26th, 2012; accepted February 9th, 2012
ABSTRACT
Background: While neuropsychological deficits are common in patients with end stage liver disease (ESLD) evaluated
for transplantation, the determinant factors are not clear. Methods: Towards that end, we examined data from 108 pa-
tients who completed neuropsychological tests as part of their liver transplantation evaluation. First, controlling for es-
timated premorbid ability and mood, multiple regression analyses were used to examine the effects of illness severity on
cognition. Second, we compared neuropsychological functioning of patients with vs. without a history of excessive al-
cohol use, independent of primary liver disease diagnosis. Results: Severity of illness was associated with the extent of
psychomotor slowing. Excessive alcohol use was associated with lower scores on tests of memory. Furthermore, worse
memory was not explained by lower estimated premorbid ability, lower concurrently measured general intelligence, or
greater illness severity. Conclusions: Our findings illustrate the importance of controlling for estimated premorbid abil-
ity in assessing the effect of illness variables on cognition. Another implication is that measures of psychomotor speed
are important in assessing cognition in patients with ESLD, and especially for patients with a history of excessive alco-
hol use, a broader range of domains, including memory, should be examined.
Keywords: Liver Disease; Cognition
1. Introduction
Liver disease is a major cause of death in the United States.
For example, in 2007 it was the fourth leading cause of
death in people ages 45 to 54 years [1]. The most com-
mon causes of liver disease are heavy alcohol consump-
tion and hepatitis C. Other etiologies include hepatitis B,
nonalcoholic fatty liver disease, autoimmune hepatitis,
diseases that damage or destroy the bile ducts, inherited
diseases, and fulminant liver failure due to toxicity.
Cognitive impairment, affective symptoms, and com-
promised quality of life are common consequences of
chronic liver disease [2,3]. Cognitive impairment from liver
disease, furthermore, is associated with increased socio-
economic (employment, finances) and caregiver burden
[2]. Hepatic encephalopathy (HE) is characterized by de-
ficits in multiple cognitive domains and may progress to
acute confusion or coma. While HE typically responds to
treatment targeting the suspected underlying metabolic
causes, it can lead to neurobehavioral dysfunction that
does not completely resolve after liver transplantation [4-6].
Many patients experience milder cognitive dysfunction,
commonly referred to as minimal hepatic encephalopathy
(MHE). MHE is primarily characterized by a deficit in
cognitive processing speed that is apparent on select neuro-
psychological tests rather than standard mental status
exam (for review, see Randolph et al. [7]). Early detec-
tion and management of patients with MHE is important
because of the increased risk of developing overt hepatic
encephalopathy and gross cognitive impairment.
Recently, the International Society on Hepatic Encepha-
lopathy and Nitrogen Metabolism convened a group of
experts to recommend approaches for the routine neuro-
psychological assessment of patients with liver disease.
In their practice guidelines [7] the commission recom-
mended two specific batteries, the PSE-Syndrom-Test [8]
and the Repeatable Battery for the Assessment of Neuro-
psychological Status (RBANS) [9]. The PSE-Syndrom-
Test consists of five measures of psychomotor speed.
*Corresponding author.

Effects of Illness Severity and Alcohol Use on Cognition in End Stage Liver Disease after
Controlling for General Intelligence and Mood
126
The RBANS measures several cognitive domains and has
been validated for use with a variety of patient groups
that evidence neurobehavioral dysfunction.
Patients with ESLD exhibit a range of deficits on the
RBANS. Sorrell et al. [10] examined cognitive function-
ing in 300 consecutive outpatients presenting for liver
transplantation evaluation using the RBANS and the Trail-
Making Test (TMT), a measure of psychomotor speed re-
quiring executive function (attentional shifting). Worse
test scores were associated with greater severity of liver
disease as measured by MELD (measure of end-stage
liver disease) score. The authors identified the pattern of
deficits on RBANS Index scores as being consistent with
subcortical brain dysfunction. After controlling for the
severity of liver disease, patients with a history of alco-
hol abuse or dependence performed more poorly on the
RBANS and TMT than those patients without such a his-
tory. However, group differences were only examined for
the RBANS Total score and not the five Index scores. In
a similar study, Mooney et al. [11] found that patients
with ESLD performed below expectation on the RBANS
compared to the healthy standardization sample [9]. Con-
sistent with Sorrell et al. [10] they identified a subcortical
pattern of impairment on the RBANS. However, there
were no significant differences among diagnostic groups,
including those that varied by alcohol etiology, in analy-
ses which controlled for estimated premorbid verbal in-
telligence. This study did not examine cognitive perform-
ance as a function of illness severity.
Both of the above studies demonstrated neuropsycho-
logical deficits in patients with ESLD, but neither study
examined the effect of illness severity on cognition after
controlling for estimated premorbid ability and symptoms
of depression and anxiety. Both studies focused on pa-
tient groups classified by primary diagnosis (e.g., alco-
holic liver disease, hepatitis C with or without alcoholic
liver disease, cholestatic liver disease). The findings re-
garding the importance of alcohol history were inconsis-
tent, and the cognitive domains from the RBANS most
likely to differentiate those patients with vs without a
history of alcohol abuse or dependence remains unclear.
While the etiology of liver disease is important, the
extent of prior alcohol consumption may be a more criti-
cal determinant of cognitive status among patient with
ESLD. Chronic excessive alcohol consumption is associ-
ated with decreased cortical gray matter volume, shrink-
age of select subcortical regions (e.g., thalamus, hippo-
campus, mammillary bodies), demyelination, and axonal
degeneration [12]. Longitudinal MRI studies have shown
that with abstinence brain volume loss is partially reverse-
ble, especially in frontal and temporal regions, although
one factor that diminishes recovery is concurrent hepatic
disease [13].
The RBANS is sensitive to deficits in memory, psy-
chomotor speed, verbal fluency and visuospatial ability
in moderate to heavy active alcohol users [14]. Persistent
cognitive deficits following abstinence include memory
and executive dysfunction [12]. Because the RBANS
does not assess executive function, the TMT is often in-
cluded in assessments of patients with ESLD who have a
history of alcohol abuse [10].
To the extent that chronic excessive alcohol consump-
tion causes cognitive impairment independent of liver dis-
ease, the pattern of dysfunction in liver disease patients
with vs. without a history of alcohol abuse or dependence
will likely differ. For this reason, it is useful to assess
neuropsychological functioning in ESLD patients by al-
cohol status independent of the primary liver disease di-
agnosis. Such information, in turn, may inform assessment
and management practices for these different liver disease
populations.
In this study we examined the neuropsychological func-
tioning of patients being evaluated for liver transplanta-
tion as a function of illness severity, after controlling for
estimated premorbid ability, depression, and anxiety. We
also expanded on prior research by including a brief
measure of general intelligence as well as the RBANS
and TMT as dependent variables. Our principal aim was
to compare patient groups classified by the presence vs.
absence of a history of alcohol abuse or dependence, in-
dependent of the primary liver disease diagnosis. We hy-
pothesized that patients with a history of alcohol abuse or
dependence would exhibit greater neuropsychological dys-
function than those without such a history. Given the
well-known effects of alcoholism on cognition, we antici-
pated that RBANS memory would be particularly sensi-
tive to group differences.
2. Methods
2.1. Participants
Participants were 108 adults who were being evaluated for
orthotopic liver transplantation at a large, urban medical
center in central Virginia. They were mostly male (70.4%)
and Caucasian (82.4%), with 13.7% African American
and 3.7% Hispanic. Mean age was 53.3 (SD = 7.5) and
mean education level was 12.8 years (SD = 2.4). About
32% of patients were actively employed, 42% disabled,
10% retired, and the remainder unemployed or not ac-
tively working. All participants completed a comprehen-
sive multidisciplinary evaluation by a hepatologist, trans-
plant surgeon, clinical psychologist and social worker.
Medical history, physical exam, laboratory studies, clinical
interview and mental status exam were used to identify
etiology and severity of liver disease, comorbid medical
conditions, psychiatric disorders, history of substance use,

Effects of Illness Severity and Alcohol Use on Cognition in End Stage Liver Disease after
Controlling for General Intelligence and Mood
127
cognitive impairment, current health behaviors and treat-
ment status. Individuals were excluded from this study if
cognitive impairment was attributed to neurologic disor-
ders (e.g., traumatic brain injury), acute medical illness
other than liver disease, or poorly managed psychiatric
disorders. Individuals were also excluded if English was
not their primary language. Liver diagnoses in our sam-
ple were: 40.7% Hepatitis C, 25% alcoholic cirrhosis,
and 34.3% other (e.g., sarcoidosis, cryptogenic, biliary
cirrhosis). This study was approved by the Virginia Com-
monwealth University Institutional Review Board.
2.2. Measures and Procedures
All patients completed a clinical interview, self-report in-
ventory, and neuropsychological tests, as described be-
low. Tests were administered by a doctoral level psy-
chologist (second author) or a doctoral trainee under the
supervision of the psychologist. The MELD score [15]
was used to assess severity of liver disease. The diagno-
sis of alcohol abuse or dependence was made after the
clinical interview, using criteria set forth in the Diagnos-
tic and Statistical Manual of Mental Disorders-Fourth
Edition [16].
Neuropsychological tests. General intellectual ability
was assessed using the Vocabulary and Matrix Reason-
ing subtests from the Wechsler Abbreviated Scale of
Intelligence (WASI) [17]. These two subtests have a high
factor loading on g (general intelligence factor) and yield
an estimated Full Scale IQ (FSIQ) score. The Wechsler
Test of Adult Reading (WTAR) [18] demographic for-
mula was used as an estimate of premorbid FSIQ. Neuro-
psychological functioning was assessed using the RBANS
[9] and the TMT. The RBANS and TMT were selected
because of the important cognitive domains assessed,
length of time for administration that minimizes effects
of fatigue, and demonstrated utility in detecting and char-
acterizing cognitive impairment in patients with ESLD.
The RBANS yields a summary score and separate age-
adjusted index scores for immediate memory, delayed
memory, visuospatial-construction, attention and language.
The TMT is a well-established test requiring visuomotor
speed and attention [19]. In part A the individual draws
lines to connect consecutively numbered circles, and in part
B is required to connect the same number of consecu-
tively numbered and lettered circles in an alternating se-
quence. An age-corrected time score for part B was used
in the present study.
Millon Behavioral Medicine Diagnostic (MBMD). The
MBMD [20] is an inventory composed of statements an-
swered true or false that is designed to identify psycho-
social assets and liabilities which may affect an individ-
ual’s response to treatment. It includes a validity indica-
tor and response pattern scales, and norms for a general
medical population. The scores from two scales, Anxiety-
Tension and Depression, were used in the present study.
2.3. Analyses
After descriptive analyses, Pearson’s correlations between
study variables were calculated (WTAR, Anxiety, De-
pression, MELD, WASI FSIQ, RBANS Total and Index
Scores, TMT-B). We then examined the relationship be-
tween severity of liver disease and cognitive function with
three hierarchical multiple regression analyses, control-
ling for premorbid ability and mood. The independent
variables were: WTAR (Step 1), MBMD Depression and
Anxiety (Step 2), and MELD (Step 3). The dependent
variables were WASI FSIQ (Model 1), RBANS Total
(Model 2), and TMT-B time (Model 3). All neurocogni-
tive scores were age-corrected. Next, to explore the hy-
pothesis that cognitive function was significantly impaired
due to history of alcohol abuse or dependence, independ-
ent samples (i.e., positive vs negative alcohol status) t-
tests examined differences in the RBANS Total and In-
dex Scores, TMT-B, and WASI FSIQ. T-tests also ex-
amined differences by alcohol status in covariates of
WTAR, MELD and MBMD Depression and Anxiety.
SPSS v. 18.0 (Chicago, IL) was used in analyses. All
tests were 2-tailed with p < 0.05 set to indicate signify-
cance.
3. Results
The mean MELD score was 14.6 (SD = 4.9). Sixty-two
(57%) of participants reported a history of alcohol abuse
or dependence. Table 1 displays the correlations among
study variables. As shown, higher estimated premorbid
ability (WTAR) was associated with better performance
on all cognitive measures (r’s = 0.20 – 0.63). Neither
mood nor MELD scores was associated with premorbid
ability, and MELD was also not significantly correlated
with depression or anxiety (p > 0.05). Anxiety was sig-
nificantly negatively associated with overall cognitive
functioning (RBANS Total), immediate and delayed me-
mory, and language (r’s = –0.19 to –0.27) and positi-
vely associated with TMT-B time (r = 0.19), suggesting
greater anxiety is associated with poorer functioning on
these measures. Similarly, greater depression was associ-
ated with lower scores on FSIQ, RBANS Total, immedi-
ate memory and language (r’s = –0.19 to –0.22), and
longer time to complete TMT-B (r = 0.21).
Results of regression analyses (see Tabl e 2) suggested
that MELD was not significantly associated with FSIQ or
RBANS Total. The association of MELD with TMT-B
approached significance (p = 0.081). In Models 1 and 2,

Effects of Illness Severity and Alcohol Use on Cognition in End Stage Liver Disease after
Controlling for General Intelligence and Mood
128
Table 1. Correlation matrix among cognitive, mood, and severity of illness variables of patients presenting for liver trans-
plantation evaluation.
1 2 3 4 5 6 7 8 9 10 11 12
1. WTARa - 0.21† –0.15 –0.13 0.63*** 0.44*** 0.38*** 0.31** 0.30** 0.29** 0.31** –0.20*
2. MELDb - 0.02 0.10 0.05 0.06 0.04 0.18 0.01 –0.05 0.00 0.16
3. Anxietyc - 0.47*** –0.18 –0.25* –0.24* –0.14 –0.19* –0.08 –0.27** 0.19*
4. Depressionc - –0.22* –0.22* –0.19* –0.13 –0.21* –0.16 –0.16 0.21*
5. FSIQd - 0.62*** 0.43*** 0.50*** 0.50*** 0.52*** 0.40** –0.48***
6. RBANS Tote - 0.81*** 0.70*** 0.69*** 0.74*** 0.80*** –0.58***
7. RBANS- IMf - 0.36*** 0.44*** 0.51*** 0.66*** –0.46***
8. RBANS-VCg - 0.41*** 0.34*** 0.43*** –0.35***
9. RBANS-Langh - 0.45*** 0.44*** –0.43***
10. RBANS-Attni - 0.50
*** –0.49***
11. RBANS-DMj - –0.50
***
12. Trails Bk -
Note: aWTAR = Wechsler Test of Adult Reading; bMELD = Measure for End Stage Liver Disease; cAnxiety and Depression measured with Millon Behavioral
Medicine Diagnostic; dFSIQ = Wechsler Full Scale Intelligence Quotient; eRBANS Tot = Repeatable Battery for the Assessment of Neuropsychological Status
Total Score; fRBANS-IM = Immediate Memory; gRBANS-VC = Visuo-constructional; hRBANS-Lang = Language; iRBANS-Attn = Attention; jRBANS-DM =
Delayed Memory; kTrails B is a measure of visuomotor speed and attention. N = 108 for all variables, except for MELD score where n = 92 due to missing data.
Higher scores reflect better functioning on all measures except for Trails B and MELD: higher MELD is associated with worse liver disease and higher Trials B
is associated with greater impairment. †p = 0.05, *p < 0.05, **p <0.01,***p < 0.001.
Table 2. Multiple regression analyses examining the relationship among severity of liver disease and cognitive functioning; n =
92.
Variable Model 1 FSIQd Model 2 RBANSe Model 3 Trails Bk
R
2 ∆ R2 B (SE) β R 2 ∆ R2 B (SE) β R2 ∆ R2 B (SE) β
Step 1 WTARa 0.39 0.39*** 1.23 (0.16) 0.62*** 0.21 0.21*** 0.78 (0.16) 0.46*** 0.05 0.05* –0.10 (0.05) –0.22*
F (1, 89) = 56.6, p < 0.001 F (1, 89) = 24.0, p < 0.001 F (1, 89) = 4.52, p < 0.05
Step 2 WTARa 1.19 (0.17) 0.61*** 0.73 (0.16) 0.43*** –0.08 (0.05)–0.18
Depressionc –0.06 (0.06) –0.10 –0.05 (0.06) –0.10 0.03 (0.02) 0.20
Anxietyc
0.40 0.01
–0.02 (0.06) –0.03
0.24 0.02
–0.04 (0.06) –0.08
0.11 0.07
0.01 (0.02) 0.07
F (3, 87) = 19.4, p < 0.001 F (3, 87) = 8.94, p < 0.001 F (3, 87) = 3.42, p < 0.05
Step 3 WTARa 1.22 (0.17) 0.62*** 0.74 (0.16) 0.44*** –0.10 (0.05)–0.22*
Depressionc –0.05 (0.06) –0.09 –0.05 (0.06) –0.09 0.02 (0.02) 0.18
Anxietyc –0.02 (0.06) –0.03 –0.04 (0.06) –0.08 0.01 (0.02) 0.07
MELDb
0.40 0.00
–0.21 (0.29) –0.06
0.24 0.00
–0.06 (0.28) –0.02
0.14 0.03÷
0.14 (0.08) 0.18÷
F(4, 86) = 14.6, p < 0.001 F (4, 86) = 6.65, p < 0.001 F (4, 86) = 3.40, p < 0.05
Note: All scores are age-corrected, thus age is not included as a covariate. Analyses include 92 patients with MELD scores available. No differences
were found between patients with and without recorded MELD scores. aWTAR = Wechsler Test of Adult Reading; bMELD = Measure for End Stage
Liver Disease; cAnxiety and Depression measured with Millon Behavioral Medicine Diagnostic; dFSIQ = Wechsler Full Scale Intelligence Quotient;
eRBANS = Repeatable Battery for the Assessment of Neuropsychological Status-Total score used in analyses; kTrails B is a measure of visuomotor
speed and attention. *p < 0.05, **p < 0.01, ***p < 0.001, ÷p = 0.081.
estimated premorbid ability was the only variable signifi-
cantly associated with FSIQ and RBANS Total, explain-
ing 62% and 44% of the variance, respectively. The ad-
dition of depression and anxiety (Step 2) and MELD (Step
3) did not increase the explanatory power of the models
(nonsignificant ∆R2). In Model 3 premorbid ability was

Effects of Illness Severity and Alcohol Use on Cognition in End Stage Liver Disease after
Controlling for General Intelligence and Mood
129
significantly negatively associated with TMT-B time (β =
–0.26), suggesting better performance with higher pre-
morbid ability. Thus in each model, higher premorbid
ability was associated with better performance on the
tests of cognitive function, explaining the majority of the
variance in the outcomes. Severity of liver disease only
explained a marginally significant amount of the variance
(18%) in psychomotor speed (i.e., TMT-B) and was not
associated with either overall intellectual functioning
(WASI FSIQ) or overall neuropsychological functioning
(RBANS Total). Depression and anxiety explained a small
but nonsignificant amount of the variance in each outcome.
Table 3 displays liver diagnoses, MELD scores, and
cognitive and mood variables by history of alcohol abuse/
dependence. Patients with a history of alcohol use/depen-
dence were more likely to have Hepatitis C as well as al-
coholic cirrhosis, compared with other diagnoses. Esti-
mated premorbid ability and MELD scores were similar
on the two groups. Patients with a history of alcohol use
reported greater depression and had lower scores on mea-
sures of immediate and delayed memory than patients
without a history of alcohol abuse/dependence.
4. Discussion
Results of this study underscore the importance of as-
sessing alcohol history in patients presenting for liver
transplantation evaluation. Specifically, those individuals
with a history of excessive alcohol use scored lower on
RBANS measures of memory. Lower memory scores
were not explained by lower estimated premorbid intel-
ligence or lower WASI FSIQ, which were similar for the
alcohol and non-alcohol groups. This finding is consis-
tent with well-known effects of alcoholism on brain func-
tion. That is, impaired explicit memory, especially on tests
of free recall, is a salient persistent deficit associated with
alcoholism [12]. Patients with vs without a history of ex-
cessive alcohol use did not differ in illness severity, as
measured by MELD scores (see Table 3). However, it
remains possible that the relation between alcohol and
illness severity was mitigated by self-report bias at the
time of the transplant evaluation. Depression may also
have been a contributing factor. Depression was associ-
ated with worse performance on several cognitive tests
and those individuals with a history of alcohol abuse or
dependence reported higher levels of depression.
Severity of liver disease was marginally associated with
psychomotor speed, consistent with the findings of Sorrell
et al. [10]. The relationship between illness severity and
psychomotor speed was independent of the effects of
premorbid ability and mood. Specifically, liver disease
severity explained 18% of the variance on TMT-B scores,
Table 3. Liver diagnosis and cognitive functioning by alcohol abuse/dependence status.
Variable Alcohol n = 62 No Alcohol n = 46
Diagnosis
Hepatitis C (%) 43.5 37.0
Alcoholic Cirrhosis (%) 41.9 2.2
Other (%) 14.5 60.9
MELD Scoreb 14.9 (5.0) 14.1 (4.7)
Premorbid IQ-WTARa 101.6 (8.4) 101.6 (7.8)
WASI-FSIQd 95.0 (16.3) 95.8 (16.4)
RBANS-Totale 81.2 (13.7)± 86.4 (14.1)
Immediate Memory 83.2 (15.9)** 92.0 (16.2)
Visuo-constructional 84.6 (18.9) 85.8 (15.8)
Language 89.7 (9.8) 92.2 (12.5)
Attention 84.7 (14.6) 86.2 (15.7)
Delayed Memory 85.5 (14.8)* 92.2 (15.0)
Trails B (z-score)k 2.4 (3.7) 1.49 (3.3)
MBMD Anxietyc 46.9 (27.1) 38.6 (25.6)
MBMD Depressionc 53.6 (27.3)* 41.1 (27.5)
Note: Data are Mean (SD), unless otherwise indicated. Scaled scores of measures are reported. Significance tests indicate differences on variable by alcohol
abuse/dependence vs no alcohol abuse/dependence, calculated with independent samples t-tests or one-way ANOVAs. aWTAR = Wechsler Test of Adult
Reading; bMELD = Measure for End Stage Liver Disease; cAnxiety and Depression measured with Millon Behavioral Medicine Diagnostic; dFSIQ = Wechsler
Full Scale Intelligence Quotient; eRBANS Total = Repeatable Battery for the Assessment of Neuropsychological Status Total Score; kTrails B is a measure of
visuomotor speed and attention. ±p = 0.055, *p < 0.05, **p < 0.01.

Effects of Illness Severity and Alcohol Use on Cognition in End Stage Liver Disease after
Controlling for General Intelligence and Mood
130
after controlling for estimated premorbid intelligence and
self-reported depression and anxiety. In contrast, severity
of liver disease was not associated with measures of gen-
eralized cognitive impairment (i.e. RBANS Total score
and WASI FSIQ). Sorrell et al. [10] did find a correlation
between MELD and RBANS Total score, but the asso-
ciation was weak (Pearson correlation = –0.20). Further-
more, a strength of our study is that we controlled for
depression, anxiety, and estimated premorbid ability, the
latter of which was significantly related to performance
on all the dependent variables in our regression analyses.
Our findings illustrate the importance of taking into
account estimated premorbid ability in assessing the ef-
fect of illness variables on cognitive test performance.
Estimated premorbid ability was the only variable asso-
ciated with not only WASI FSIQ but also RBANS Total
score, explaining 62% and 44% of the variance, respec-
tively. Estimated premorbid ability also explained 22%
of the variance on TMT-B scores.
Individuals with MHE and HE often report symptoms
of depression and anxiety. While simple correlations
showed that both depression and anxiety were negatively
associated with cognitive performance, in regression ana-
lyses depression and anxiety explained only small, non-
significant amount of the variance in each outcome
measure. Also, greater illness severity was not associated
with higher levels of anxiety or depression.
Limitations of our study include the use of a demo-
graphic formula to estimate premorbid intelligence with-
out the concurrent measure of reading skills on the WTAR.
However, both demographic indices and reading achieve-
ment tests are commonly used without the other to esti-
mate premorbid intelligence, and the demographic for-
mula used in this study was the only variable reliably
related to all three neuropsychological measures in the
regression analyses. Current intellectual ability was as-
sessed using two WASI subtests and the obtained score is
only an estimate of FSIQ. While about 14% of the sam-
ple was African-American, it was not otherwise repre-
sentatve of the diversity of the US population. In order
for our findings to be as generalizable as possible to the
population of liver disease patients evaluated for ortho-
topic liver transplantation, we did not exclude individuals
with comorbid medical disorders unless there was an acute
illness felt to be the cause of observed cognitive dysfunc-
tion. Nevertheless, the relationship between MELD scores
and cognitive test scores may have been attenuated by
the presence of comorbid medical disorders. However, this
study has multiple strengths including control for esti-
mated premorbid ability and mood in regression analyses,
inclusion of a concurrent measure of general intelligence,
and the comparison of patient groups classified by alco-
hol status independent of primary liver disease diagnosis.
In summary, our findings suggest a negative relation-
ship between illness severity and psychomotor speed, and
between excessive alcohol use and memory, in patients
with ESLD. One important implication of these findings
is that different neuropsychological tests might be used
to efficiently screen cognitive abilities in individuals be-
ing evaluated for liver transplantation, depending on their
history of alcohol use. Tests such as the RBANS are par-
ticularly important in assessing those individuals with
known or suspected history of excessive alcohol use, re-
gardless of the primary liver disease diagnosis. In those
individuals without a significant drinking history, meas-
ures of psychomotor or information processing speed may
have greater utility. The sensitivity of such speed tests to
the effects of liver disease of various etiologies is an im-
portant area of ongoing research, especially for individu-
als at risk for MHE who may be more amendable to treat-
ment with lactulose and other therapies.
REFERENCES
[1] J. Xu, K. D. Kochanek, S. L. Murphy and B. Tejada-Vera,
“Deaths: Final Data for 2007. National Vital Statistics
Reports,” National Center for Health Statistics, Hyat-
tsville MD, Vol. 58, No. 19, 2010.
[2] J. S. Bajaj, J. B. Wade, D. P. Gibson, D. M. Heuman, L.
R. Thacker, R. K.Sterling, et al., “The Multi-Dimensional
Burden of Cirrhosis and Hepatic Encephalopathy on Pa-
tient and Caregivers,” The American Journal of Gastro-
enterology, Vol. 106, No. 9, 2011, pp. 1646-1653.
doi:10.1038/ajg.2011.157
[3] S. Mechtcheriakov, I. W. Graziadei, A. Kugener, J.
Wiedemann, C. Galbavy, H. Hinterhuber, et al., “Multi-
dimensional Assessment of Neuropsychiatric Symptoms
in Patients with Low-Grade Hepatic Encephalopathy: A
Clinical Rating Scale,” World Journal of Gastroenterol-
ogy, Vol. 11, No. 37, 2005, pp. 5893-5898.
[4] F. Campagna, A. Biancardi, U. Cillo, A. Gatta and P.
Amodio, “Neurocognitive-Neurological Complications of
Liver Transplantation: A Review,” Metabolic Brain Dis-
ease, Vol. 25, No. 1, 2010, pp. 115-124.
doi:10.1007/s11011-010-9183-0
[5] M. B. Lewis and P. D. Howdle, “Cognitive Dysfunction
and Health-Related Quality of Life in Long-Term Liver
Transplant Survivors,” Liver Transplantation, Vol. 9, No.
11, 2003, pp. 1145-1148. doi:10.1053/jlts.2003.50239
[6] S. Mechtcheriakov, I. W. Graziadei, M. Mattedi, T. Bod-
ner, A. Kugener, H. Hinterhuber, et al., “Incomplete Im-
provement of Visuo-Motor Deficits in Patients with
Minimal Hepatic Encephalopathy after Liver Transplan-
tation,” Liver Transplantation, Vol. 10, No. 1, 2004, pp.
77-83. doi:10.1002/lt.20009
[7] C. Randolph, R. Hilsabeck, A. Kato, P. Kharbanda, Y. Li,
D. Mapelli, et al., “Neuropsychological Assessment of
Hepatic Encephalopathy: ISHEN Practice Guidelines,”
Liver International, Vol. 29, No. 5, 2009, pp. 629-635.

Effects of Illness Severity and Alcohol Use on Cognition in End Stage Liver Disease after
Controlling for General Intelligence and Mood
131
doi:10.1111/j.1478-3231.2009.02009.x
[8] H. Schomerus, K. Weissenborn, W. Hamster, N. Ruckert
and H. Hecker, “PSE-Syndrome Test,” Swets & Zei-
tlinger BV, Frankfurt, 1999.
[9] C. Randolph, “Repeatable Battery for the Assessment of
Neuropsychological Status Manual,” The Psychological
Corporation, San Antonio, 1998.
[10] J. H. Sorrell, B. J. Zolnikov, A. Sharma and I. Jinnai,
“Cognitive Impairment in People Diagnosed with End-
Stage Liver Disease Evaluated for Liver Transplantation,”
Psychiatry and Clinical Neurosciences, Vol. 60, No. 2,
2006, pp. 174-181.
doi:10.1111/j.1440-1819.2006.01483.x
[11] S. Mooney, T. I. Hasssanein, R. C. Hilsabeck, E. A.
Ziegler, M. Carlson, L. M. Maron, et al., “Utility of the
Repeatable Battery for the Assessment of Neuropsy-
chological Status (RBANS) in Patients with End-Stage
Liver Disease Awaiting Liver Transplant,” Archives of
Clinical Neuropsychology, Vol. 22, No. 2, 2007, pp. 175-
186. doi:10.1016/j.acn.2006.12.005
[12] E. V. Sullivan, A. Harris and A. Pfefferbaum, “Alcohol’s
Effects on Brain and Behavior,” Alcohol Research and
Health, Vol. 33, No. 1-2, 2010, pp. 127-143.
[13] P. H. Yeh, S. Gazdzinski, T. C. Durazzo, et al., “Hierar-
chical Linear Modeling (HLM) of Longitudinal Brain
Structural and Cognitive Changes in Alcohol-Dependent
Individuals during Sobriety,” Drug and Alcohol Depend-
ence, Vol. 91, No. 2-3, 2007, pp. 195-204.
doi:10.1016/j.drugalcdep.2007.05.027
[14] A. Green, T. Garrick, D. Sheedy, H. Blake, E. A. Shores
and C. Harper, “The Effect of Moderate to Heavy Al-
cohol Consumption on Neuropsychological Performance
as Measured by the Repeatable Battery for the Assess-
ment of Neuropsychological Status,” Alcoholism Clinical
and Experimental Research, Vol. 34, No. 3, 2010, pp.
443- 450. doi:10.1111/j.1530-0277.2009.01108.x
[15] R. S. Brown, K. S. Kumar, M. W. Russo, M. Kinkhab-
wala, D. L. Rudow, P. Harren, et al., “Model for End-
Stage Liver Disease and Child-Turrotte-Pugh Score as
Predictors of Pretransplantation Disease Severity, Post-
transplantation Outcome, and Resource Utilization in
United Network for Organ Sharing Status 2A Patients,”
Liver Transplantation, Vol. 8, No. 3, 2002, pp. 278-284.
doi:10.1053/jlts.2002.31340
[16] American Psychiatric Association, “Diagnostic and Sta-
tistical Manual of Mental Disorders,” 4th Edition, Ame-
rican Psychiatric Association, Washington DC, 1994.
[17] D. Wechsler, “Wechsler Abbreviated Scale of Intelligence,”
The Psychological Corporation, San Antonia, 1999.
[18] D. Wechsler, “Wechsler Test of Adult Reading (WTAR),”
The Psychological Corporation, San Antonio, 2001.
[19] M. D. Lezak, “Neuropsychological Assessment,” Oxford
University Press, New York, 1983.
[20] T. Millon, M. Antoni, C. Millon, S. Meagher and S. Gro-
ssman, “Millon Behavioral Medicine Diagnostic,” NCS
Assessments, Minneapolis, 2001.