Health-Related Quality of Life Predicts Mortality in Patients With

Advanced Chronic Liver Disease

FASIHA KANWAL,*
,,
IAN M. GRALNEK,

RON D. HAYS,
,#
ANGELIQUE ZERINGUE,* FRANCISCO DURAZO,**
STEVEN B. HAN,**
,
SAMMY SAAB,** ROGER BOLUS,

and BRENNAN M. R. SPIEGEL

,,
**
,
*John Cochran VA Medical Center, St. Louis, Missouri;

Division of Gastroenterology, Saint Louis University, St. Louis, Missouri;

UCLA/VA Center for Outcomes
Research and Education at UCLA, Los Angeles, California;

Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Rambam Health Care Campus,
Haifa, Israel;

Department of Health Services, UCLA School of Public Health, Los Angeles, California;
#
RAND, Santa Monica, California; **Division of Digestive
Diseases, David Geffen School of Medicine at UCLA, Los Angeles, California; and

Department of Gastroenterology & Hepatology, VA Greater Los Angeles
Healthcare System, Los Angeles, California
BACKGROUND&AIMS: It is well-established that cirrho-
sis negatively impacts health-related quality of life (HRQOL).
However, it is less clear how to use this information in everyday
clinical practice. If HRQOL predicted survival in cirrhosis, then
measuring HRQOL would have important clinical implications.
We sought to measure the association between HRQOL and
survival in patients with cirrhosis and investigated whether the
relationship between HRQOL and survival is independent of
Model for End-Stage Liver Disease (MELD). METHODS: We
measured HRQOL in 156 patients with cirrhosis awaiting liver
transplantation by using the Short Form Liver Disease Quality
of Life instrument. We followed patients prospectively and used
Cox proportional hazard models to measure the independent
effect of baseline HRQOL on survival, adjusting for MELD and
other covariates. RESULTS: During a mean 9-month follow-
up, 26 (17%) patients died, and 30 (20%) received liver trans-
plants. In unadjusted analysis, higher baseline HRQOL predicted
lower mortality (hazard ratio, 0.96; 95% condence interval, 0.94
0.99). Specically, for each 1-point increase in HRQOL, there was
a 4% decrease in mortality. These results did not change after
adjusting for MELD scores, patient demographics, or psychos-
ocial characteristics; the MELD score accounted for 1% of the
variation in HRQOL scores (P .18). Survival was most
strongly predicted by activities of daily living, health distress,
sleep disturbance, and perceived disease stigma. CONCLU-
SIONS: Higher HRQOL predicts lower mortality in pa-
tients with cirrhosis. This relationship is independent of
MELD; MELD does not capture liver-specic HRQOL. Be-
yond its use as a secondary outcome in clinical trials,
HRQOL could be used to predict survival of patients with
advanced liver disease.
C
irrhosis is a prevalent and expensive condition, affecting
5.5 million patients at a cost of more than $1.5 billion
annually in the US.
13
Cirrhosis is the second leading cause of
digestive diseaserelated mortality, preceded only by colorectal
cancer.
2
This human and economic burden of illness is multi-
plied by the dramatic impact of cirrhosis on health-related
quality of life (HRQOL) resulting from complications of ad-
vanced liver disease, including encephalopathy, ascites, varices,
and hepatocellular cancer.
410
Thus, the burden of disease en-
gendered by cirrhosis extends beyond its impact on traditional
biologic outcomes to include a negative impact on patient-
reported outcomes such as HRQOL.
Despite the realization that HRQOL is an important out-
come in patients with cirrhosis, clinicians rarely assess HRQOL
in clinical practice. One explanation for this disconnect might
be a perceived lack of clinical actionability of HRQOL data, in
contrast to objective disease indices such as the Model for
End-Stage Liver Disease (MELD) score.
11,12
Whereas MELD ac-
curately predicts mortality in cirrhosis and guides decision-
making for transplantation,
12
it is unclear whether HRQOL
provides the same predictive value, or whether it can augment
MELD-based prediction in any clinically meaningful way. Yet in
other chronic diseases such as end-stage renal disease, conges-
tive heart failure, and cancer, among others, HRQOL is a
consistent predictor of mortality.
1319
It is possible that HRQOL
might also predict mortality in cirrhosis, although this hypoth-
esis is untested.
If HRQOL could predict mortality independent of MELD,
then it would suggest that HRQOL might augment MELD by
providing incremental predictive ability not captured by tradi-
tional biologic indices. Moreover, HRQOL might complement
MELD in identifying high-risk patients and help in making
decisions about how best to allocate resources among different
patient groups. Therefore, we sought to measure the predictive
value of HRQOL in a prospective cohort of patients with
cirrhosis and investigated whether the relationship between
HRQOL and survival is independent of MELD.
Methods
Study Subjects
We conducted a prospective study of 156 consecutive
patients with cirrhosis awaiting liver transplantation at the
UCLA-Dumont Liver Transplant Program in Los Angeles, Cal-
ifornia between March of 2004 and June of 2006. We excluded
subjects if they were 18 years old, had previously received a
liver transplant, or had at least grade 2 hepatic encephalopathy
despite optimal medical management. This study was approved
Abbreviations used in this paper: CI, condence interval; HR, hazard
ratio; HRQOL, health-related quality of life; MCS, mental composite
summary score; MELD, Model for End-Stage Liver Disease; PCS, phys-
ical composite summary score; SD, standard deviation; SF-LDQOL,
Short Form Liver Disease Quality of Life.
2009 by the AGA Institute
1542-3565/09/$36.00
doi:10.1016/j.cgh.2009.03.013
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2009;7:793799
by the Institutional Review Board at the University of Califor-
nia, Los Angeles.
Health-Related Quality of Life Measures
We measured HRQOL by using a liver diseasetargeted
instrument, the Short Form Liver Disease Quality of Life (SF-
LDQOL).
20
The SF-LDQOL is a short form version of the Liver
Disease Quality of Life Version 1.0 (LDQOL 1.0) instrument.
21
The LDQOL 1.0 was developed and evaluated in a cross-sec-
tional, multicenter study including 221 patients with advanced
liver disease.
21
With HRQOL data from the original psychomet-
ric evaluation of the LDQOL 1.0, a subset of the LDQOL 1.0
items was selected for the SF-LDQOL on the basis of the
maximum R
2
regression and internal consistency reliability co-
efcients.
22
Detailed psychometric evaluations provided strong
support for the reliability, construct validity, and responsive-
ness of the SF-LDQOL.
20
The disease-targeted scales of the SF-LDQOL include 36
items measuring 9 scales, including liver diseaserelated symp-
toms, liver diseaserelated effects on activities of daily living,
concentration/memory, health distress, sleep, loneliness, hope-
lessness, self-perceived stigma of liver disease, and sexual func-
tioning/problems. These are combined into an overall SF-
LDQOL score that summarizes the overall disease-targeted
HRQOL with a single number ranging from 0100, with higher
score indicating better HRQOL. Similar to the LDQOL 1.0, the
SF-LDQOL uses the SF-36 version 2.0 as the generic core.
23
The
SF-36 instrument includes 8 multi-item scales (physical func-
tioning, physical role limitations, emotional role limitations,
bodily pain, general health, emotional well-being, energy/fa-
tigue, and social functioning) and can be aggregated into 2
summary scores: (1) physical component score (PCS) and (2)
mental component score (MCS).
23
With the exception of items included in the sexual function-
ing/problems scales, data were missing for less than 5% of the
items. Because the sexual functioning/problem scale applies
only to the subset of population with recent sexual activity (ie,
within the previous 4 weeks), these items were completed by
only 49% of patients in our cohort. For these patients, we
followed the standard HRQOL scoring procedure and calcu-
lated the HRQOL scores by using the items that the respondent
answered.
24
Mortality Assessment
We followed all participants longitudinally and termi-
nated the follow-up at the time of the patients death, liver
transplantation, or December 31, 2006, whichever occurred
rst.
As part of the study protocol, patients were followed up once
during their routine clinic visits 6 months after their enroll-
ment. Subsequent follow-up was based on medical chart review.
To maximize ascertainment of mortality in the study subjects,
we contacted patients who were alive at their last recorded visit
by telephone or mail and obtained information on their status
before the end of the study.
Control Variables
On the basis of a priori hypotheses guided by data from
the literature, we specied relevant factors that might affect
patient survival while awaiting liver transplantation. These in-
cluded sociodemographic characteristics (age, race, household
income, marital status, education level, employment), liver dis-
easerelated characteristics (etiology of liver disease, MELD
score, diagnosis of liver cancer, ascites, hepatic encephalopathy,
serum sodium, dialysis), and comorbidity-related characteristics
(Charlson Comorbidity Index).
11,12,2528
The Charlson Comor-
bidity Index is a weighted index that takes into account the
number and the seriousness of comorbid diseases,
28
with a
stepwise increase in the risk of 1-year mortality that ranges
from 12% for 0 score to 26% with scores 12, 52% with scores
34, and 85% with scores 5. Charlson Index denes liver
disease patients as having either mild or moderate/severe dis-
ease. Because all patients in this study had complicated liver
disease, we assumed they all received a 3 on the liver component
of the score, where 3 is moderate/severe and 1 is mild liver
disease. We computed MELD scores for all patients according
to published algorithms.
11,12
Table 1 provides the full list of
patient factors and their method of categorization.
Statistical Analysis
We analyzed patient data by using SAS, version 9.1 (SAS
Inc, Cary, NC). All P values were two-sided, with an alpha of .05
as the standard for determining signicance. With bivariate Cox
proportional-hazards models, we rst estimated the unadjusted
relationship between each covariate and mortality. We next
measured the independent relationship between HRQOL and
mortality, while adjusting for predictors of mortality. We per-
formed a Cox multivariable proportional-hazard model by us-
ing a backward stepwise procedure for selecting variables, re-
taining those with P .1. We computed the adjusted hazard
ratios (HRs) and 95% condence intervals (CIs) to estimate the
strength of association of each predictor with time to death. To
test the robustness of our ndings, we performed a separate
model by using a forward stepwise procedure. The purpose of
this was to evaluate the convergency between the forward and
backward models. With logistic regression analyses, we calcu-
lated the relative risk of death for patients with varying degrees
of HRQOL decrement compared with those with average
HRQOL, while adjusting for liver disease severity. We calculated
bootstrap 95% CIs around the point estimate by using 1000
sampling iterations. Finally, we used linear regression analysis
to measure the proportion of variance of SF-LDQOL captured
by MELD scores. The purpose of this analysis was to determine
whether MELD is a sufcient proxy measure for liver-specic
HRQOL.
Results
Baseline Characteristics
The mean age standard deviation (SD) of eligible
patients was 53.9 11 years, and 55% were male. Sixty-six
percent were white, 6% black, and 5% Asian. Table 1 summarizes
other key sociodemographic characteristics. The most common
etiologies for cirrhosis included viral hepatitis (47%), metabolic
or cryptogenic liver diseases (28%), autoimmune liver diseases
(13%), and alcohol-related liver disease (10%). At baseline, 32%
had moderate to severe ascites, 45% had grade 1 encephalopa-
thy, and 32% had a history of prior variceal hemorrhage. Nine
percent had hepatocellular cancer, and 14% were receiving he-
modialysis. Because we counted advanced liver disease in our
calculation, the Charlson Comorbidity Index was high for our
cohort (median, 4; interquartile range, 35). The baseline serum
794 KANWAL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 7
sodium was 139 4.8 mEq/1, and MELD score was 18.5 3.9.
When administered together with the SF-36 generic core, the
SF-LDQOL required 18 9 minutes to complete. The baseline
SF-LDQOL, PCS, and MCS scores were 55.3 19, 30.8 11,
and 41.0 11, respectively.
Eighty-six patients completed the 6-month clinic follow up.
For the remaining patients, we relied on medical chart review to
ascertain follow-up. We obtained information on the status of
134 subjects before the end of the study. We were unable to
contact 20 patients and thus censored their follow-up at the last
recorded visit. Of these, only 4 patients had 6 months of
follow-up. Two patients were lost to follow-up (ie, they did not
have repeat clinic visits and did not respond to telephone/mail
inquiry after the baseline HRQOL assessment). During a mean
of 316 days of follow-up, 26 (17%) patients died, and 30 (20%)
underwent liver transplantation.
Predictors of Mortality
Bivariate analyses. Table 2 displays the results of
the bivariate Cox proportional hazard models. Both the SF-
LDQOL (HR, 0.96; 95% CI, 0.940.99) and MELD scores (HR,
1.11; 95% CI, 1.021.21) were associated with mortality. The
results indicate that for each 1-point increase in the SF-LDQOL
score, there was a 4% decrease in mortality during the study
period. For each 1-point increase in MELD, there was an 11%
increase in mortality. Given different distributions (SF-LDQOL
range, 0100; MELD range, 640), 1-point change in the SF-
LDQOL cannot be directly compared with 1-point change in
MELD score. To allow for comparison of MELD versus SF-
LDQOL, we transformed these data into SD units. We found
that for each 1 SD increment in SF-LDQOL, there was a 54%
decrease in mortality, whereas a 1 SD increment in MELD was
associated with 48% increase in mortality.
Table 1. Baseline Sample Characteristics
Variable Results
Sociodemographic characteristics
Age, mean (y) (SD) 53.9 (11)
Gender, male (%) 54.8
Race, (%)
White 66.2
Black 5.7
Asian/Pacic Islander 4.5
Native American 1.3
Other
a
22.3
Marital status (%)
Single 15.6
Married 66.2
Separated/divorced 14.9
Widowed 3.3
Education level (%)
Eighth grade or less 11.8
Some high school 12.5
High school diploma 17.1
Some college 31.5
Professional or graduate degree 17.1
Employment status (%)
Working full-time 12.7
Working part-time 1.9
Unemployed 1.3
Retired 21.0
Disabled 48.4
Homemaker 7.0
Health insurance coverage (%)
Medicare only 4.5
Medicare and supplemental 12.1
Medicaid only 17.8
Veterans Administration 0.6
Private 5.1
HMO, PPO, IPA
b
43.9
Other 9.5
None/not sure 3.8
Total household income (%)
$5,000 6.3
$5,000$10,000 11.9
$10,001$25,000 20.9
$25,001$50,000 17.5
$50,001$75,001 16.8
$75,000 18.2
Not sure 8.4
Clinical characteristics
Primary etiology of liver disease (%)
HCV, HBV 47.4
Alcohol 10.4
PBC/PSC/AIH 13
Cryptogenic, NAFLD, HHC 28
Ascites (%)
Absent/mild 68.1
Moderate/severe 31.9
Hepatic encephalopathy (%)
Absent 55
Grade 1 45
Variceal bleeding (%)
No 68
Yes 32
Liver cancer (%)
No 91.5
Yes 8.5
Table 1. Continued
Variable Results
Dialysis (%)
No 85.7
Yes 14.2
Charlson Comorbidity Index, median
(interquartile range)
4 (35)
Serum sodium, mean (SD) 139 (4.8)
MELD score, mean (SD) 18.5 (3.9)
HRQOL, mean (SD)
LDQOL score 55.3 (18.8)
SF-36 PCS 30.8 (10.8)
SF-36 MCS 41.0 (10.8)
Patient outcomes
Died (%) 16.8
Transplanted (%) 19.5
Follow-up, mean (days) (SD) 316 (210)
Median (interquartile range) 276 (146455)
PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis;
AIH, autoimmune hepatitis; NAFLD, nonalcoholic fatty liver disease;
HHC, hereditary hemochromatosis.
a
A signicant proportion (87%) of these patients identied themselves
as Hispanic.
b
HMO, health maintenance organization; PPO, preferred provider or-
ganization; IPA, independent practice association. These represent
different models used by managed care organizations to deliver
healthcare in the US.
July 2009 HRQOL AND MORTALITY IN CIRRHOSIS 795
We next divided the patients into those with high versus low
HRQOL, stratied by the SF-LDQOL median split. We found
that patients with higher HRQOL had a 61% lower risk of death
compared with those with impaired HRQOL (HR, 0.39; 95% CI,
0.170.91). In addition to HRQOL and MELD, presence of
ascites (HR, 6.0; 95% CI, 2.6913.5) and hepatic encephalopathy
(HR, 2.0; 95% CI, 1.263.16) predicted mortality. We also found
a negative association between serum sodium and risk of death;
higher serum sodium predicted lower mortality (HR, 0.88; 95%
CI, 0.830.94). The other variables, including SF-36 PCS, MCS,
and sociodemographic variables, were not associated with mor-
tality during the study period.
Multivariate analysis. As displayed in Table 3, the
stepwise Cox proportional hazard model identied 3 signicant
predictors of mortality in our patient group. These included
SF-LDQOL (HR, 0.97; 95% CI, 0.950.99), MELD (HR, 1.11;
95% CI, 1.021.21), and presence of ascites (HR, 4.38; 95% CI,
1.8410.42). The predictors and their magnitude of association
did not change in the sensitivity analysis by using the forward
stepwise selection method. To evaluate whether using both
HRQOL and MELD would increase the predictive ability of the
model versus using either variable alone, we estimated an over-
all C index for the stepwise Cox proportional hazard model.
29
This statistic has been developed to measure model discrimi-
nation in survival analyses. This test is similar to the c statistic
except that instead of evaluating concordance between observed
and predicted probabilities, it evaluates concordance between
observed and predicted time periods between 2 patients. We
calculated the overall C index with HROQL, MELD, or both
HRQOL and MELD in the nal model (in conjunction with
ascites). The C index values for predicting mortality in our
cohort by using either MELD or HRQOL were 0.75 (95% CI,
0.640.85) and 0.74 (95% CI, 0.640.84), respectively. The C
index for the model including both MELD and HRQOL was
0.79 (95% CI, 0.700.88).
Figure 1 demonstrates the results of the logistic regression
model, stratied by varying levels of SF-LDQOL while adjusting
for liver disease severity. The data indicate that SF-LDQOL
signicantly predicted mortality at all levels. For example, those
with scores 2 SDs above the mean were approximately 60%
(relative risk, 0.42; 95% CI, 0.410.43) less likely to die versus
patients with average HRQOL. In contrast, those with scores 2
SDs below the mean were 2-fold more likely to die versus
patients with average HRQOL (relative risk, 2.07; 95% CI,
2.02.1).
To further understand the specic aspects of HRQOL most
strongly associated with mortality, we conducted additional
analyses by using the 9 scales of the SF-LDQOL in place of the
Table 3. Predictors of Mortality as Determined by Stepwise
Cox Regression Model
Variable Adjusted HR (95% CI) P value
LDQOL 0.97 (0.950.99) .039
MELD 1.11 (1.021.21) .014
Presence of moderate/severe
ascites
4.38 (1.8410.42) .0008
NOTE. This table displays results of backward stepwise regression
model. The results did not change when the analysis was repeated by
using the forward stepwise regression method.
Table 2. Associations Between Patient Baseline
Characteristics and Mortality
Variable HR 95% CI P value
Age 0.99 0.961.03 .85
Gender, male 0.66 0.31.44 .30
Race
Non-white 1.00 .10
White 2.24 0.845.97
Marital status .107
Single 1.00 0.241.14
Married 0.53
Education
High school 1.00 .72
High school 1.15 0.522.54
Health insurance coverage
Public 1.00
Private/HMO, PPO, IPA 0.66 0.301.45 .68
Total annual household
income ($)
75,000 1.00
25,00075,000 1.62 0.604.31 .33
25,000 1.44 0.494.15 .50
Primary etiology of liver
disease
HCV/HBV 1.00
Alcohol 1.72 0.555.38 .35
PBC/PSC/AIH 0.91 0.342.42 .85
Cryptogenic/NAFLD/HHC 0.95 0.273.39 .94
Ascites 1.00
Absent/mild 6.04 .0001
a
Moderate/severe 2.6913.54
Encephalopathy
No 1.00 .003
a
Yes 2.00 1.263.16
Prior variceal bleeding
No 1.00 .63
Yes 0.81 0.341.94
Liver cancer
No 1.00 .39
Yes 0.42 0.053.12
Dialysis
No 1.00 .57
Yes 0.71 0.212.37
Serum sodium 0.88 0.830.94 .0001
a
Charlson Comorbidity Index
Low (median) 1.00 .81
High (median) 0.91 0.411.99
MELD score 1.11 1.021,21 .017
a
LDQOL score 0.96 0.940.99 .01
a
SF-36 PCS 0.97 0.931.01 .15
SF-36 MCS 0.96 0.931.00 .068
NOTE. Cox proportional hazards models were used for these bivariate
analyses. HRs for age, serum sodium, MELD, LDQOL, SF-36 PCS, and
SF-36 MCS represent the risk of mortality for each 1-point change in
these variables.
HMO, health maintenance organization; PPO, preferred provider orga-
nization; IPA, independent practice association; PBC, primary biliary
cirrhosis; PSC, primary sclerosing cholangitis; AIH, autoimmune hep-
atitis; NAFLD, nonalcoholic fatty liver disease; HHC, hereditary hemo-
chromatosis.
a
Characteristics associated with patient mortality in patients with
advanced liver disease. These include presence of moderate or se-
vere ascites, presence of hepatic encephalopathy, serum sodium,
MELD, and LDQOL score.
796 KANWAL ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 7, No. 7
summary score. The following subscales were predictive of mor-
tality independent of MELD: (1) activities of daily living (HR,
0.97; 95% CI, 0.950.98); (2) health distress (HR, 0.98; 95% CI,
0.960.99); (3) sleep (HR, 0.96; 95% CI, 0.940.98); and (4)
stigma (HR, 0.98; 95% CI, 0.970.99).
To establish the relationship between SF-LDQOL and
MELD, we performed a linear regression analysis with baseline
SF-LDQOL as the dependent variable and baseline MELD as
the predictor variable. The model revealed that MELD was not
a statistically signicant predictor of SF-LDQOL (R
2
0.01;
P .18).
Discussion
The health economic burden of cirrhosis is amplied by
its impact on HRQOL, resulting from a range of physical,
psychological, and social stressors engendered by the disease
and its treatment.
410
Physically, patients with cirrhosis suffer
from debilitating symptoms including fatigue, shortness of
breath, chronic pain, poor appetite, sexual dysfunction, and
sleep abnormalities, among many others. The protean physical
manifestations of cirrhosis span nearly every organ system,
range in severity from nuisance to life-threatening, and nega-
tively disrupt patients lifestyles.
21
Psychologically, patients with
cirrhosis might have a disproportionately high incidence of
depression, often suffer from anxiety from the impending phys-
ical demise, and encounter difculties in coping with their
disease.
30,31
The ability to perform activities of daily living and
to maintain baseline social interactions is also signicantly
impaired.
21
Patients with cirrhosis are limited by dietary restric-
tions, time restrictions, and oftentimes overwhelming physical
and psychological restrictions that, taken together, can lead to
disruptions in personal relations and subsequent social with-
drawal.
21
Yet, with few exceptions, adoption of routine HRQOL
monitoring in everyday clinical practice remains suboptimal.
This disconnect between theory and practice might arise for
several reasons, including issues pertaining to the time and
effort it takes to routinely assess HRQOL in a busy clinical
setting, coupled with uncertainty about how to use HRQOL
data once collected.
Our data provide a compelling rationale for incorporating
HRQOL information into clinical decision-making in cirrhosis.
We have found that disease-targeted HRQOL provides impor-
tant prognostic information in patients with advanced liver
disease that goes beyond the information furnished by clinical
variables used in routine practice. In particular, our research has
3 key ndings.
First, we found that higher HRQOL, as measured by a liver
diseasetargeted HRQOL instrument, is associated with lower
mortality in patients with advanced liver disease. Moreover, the
predictive value of HRQOL for mortality is comparable to, if
not stronger than, that of MELD. For example, a 1 SD change
in HRQOL and MELD resulted in a similar magnitude of
change in mortality (54% vs 48%, respectively). Moreover, there
was no difference in the accuracy of predicting mortality by
using MELD or HRQOL in our sample (C index 0.75 and 0.74,
respectively). These data underscore the clinical signicance of
the observed association between HRQOL and mortality.
Second, we found that the association between disease-tar-
geted HRQOL and death in patients with cirrhosis is indepen-
dent of traditional clinical variables used to risk stratify pa-
tients. This suggests that HRQOL measurement might tap into
aspects of underlying risk or illness severity that are not fully
captured by laboratory and clinical parameters. Moreover, we
found that MELD was a poor predictor of HRQOL, capturing
only 1% of the variance in SF-LDQOL scores. Thus, MELD and
HRQOL are different concepts altogether, yet each indepen-
dently predicts mortality. Although adding HRQOL informa-
tion improved the discriminative ability of MELD-based model
in our exploratory analysis, HRQOL data are ineligible for use
in making liver allocation decisions as a result of their inher-
ently subjective nature. Regardless, these data might certainly
be useful in clinical practice to complement MELD as a predic-
tor of mortality and thus help guide decision-making in a
manner not achievable with MELD alone. For example, patients
with low HRQOL might benet from closer follow-up or en-
rollment in structured disease management programs. Such
programs are known to enhance HRQOL and reduce resource
utilization in patients with other chronic medical conditions
such as congestive heart failure.
32
In addition, HRQOL mea-
sures might help clinicians address functioning and well-being
issues beyond the scope of usual care. This is consistent with
the practice of incorporating performance status in the prog-
nostication of patients with malignancy, including hepatocel-
lular carcinoma. These practical considerations bolster the use
Figure 1. Association between liver disease-targeted
HRQOL and short-term mortality. The adjusted relative
risk of short-term mortality with 95% CI in patients with
advanced liver disease for different levels of HRQOL is
compared with the common baseline of patients with
average levels of HRQOL (mean). Data indicate that in
patients with advanced liver disease, disease-targeted
HRQOL signicantly predicts short-term mortality. For
example, patients with HRQOL 2 SD below the mean
have a 2.3 times higher risk of death compared to pa-
tients with average HRQOL. In contrast, patients with
HRQOL 2 SD above the mean are 50% less likely to die
compared to patients with average HRQOL. All levels
were statistically signicant (P .05).
July 2009 HRQOL AND MORTALITY IN CIRRHOSIS 797
of HRQOL for tracking patients over time both in clinical
practice and in clinical trials.
Third, we found that survival is most strongly associated
with activities of daily living, health distress, sleep disturbance,
and perceived disease stigma. Addressing these specic domains
through tailored behavioral interventions and disease manage-
ment programs might help improve overall HRQOL and could
potentially improve patient outcomes in a cost-effective man-
ner, although this remains untested.
Our study has several strengths. First, the patients were
drawn from clinical practice, not from a clinical trial. Therefore,
our sample is representative of patients with advanced liver
disease who are awaiting liver transplantation in routine clinical
practice. Second, we examined a wide range of patient-level
variables that might affect wait-list mortality. These included
sociodemographic characteristics, cause and severity of liver
disease, and comorbidities, among others. Third, to maximize
ascertainment of mortality in the study subjects, we did not rely
solely on clinical records, but instead we took efforts to contact
patients by telephone and mail to conrm their health status
before completing the study. Fourth, we conducted detailed
psychometric evaluations of the HRQOL instruments in our
study sample, reported elsewhere, and these assessments pro-
vide support for the reliability and validity of the SF-LDQOL.
20
Our study also has limitations. First, our sample consisted of
ambulatory patients with stable health insurance coverage and
access to healthcare. Therefore, our results might not generalize
to patients without health insurance and limited access to care.
However, because patients with limited access to healthcare are
likely to be underrepresented in any study evaluating liver
transplantation in the U.S., this weakness represents a limita-
tion of the healthcare system in general. Second, we included
patients who sought care at one tertiary care center, thus lim-
iting the applicability to patients in other healthcare facilities.
However, the liver transplant center at UCLA is one of the
largest transplant centers in the U.S. and provides care to a
demographically diverse group of patients with advanced liver
disease. Moreover, it is difcult to establish an explanation for
why the observed relationship between HRQOL and mortality
in our center would be systematically different from the rela-
tionship in other centers. Third, we excluded patients with
grade 2 hepatic encephalopathy because these patients would
have difculty completing the study questionnaire, and this, in
turn, would compromise the reliability of HRQOL scales. Ex-
clusion of subjects with hepatic encephalopathy limits the ex-
ternal validity (ie, generalizability) of our study; our ndings are
only applicable to cirrhotic patients with either no or only
clinically mild hepatic encephalopathy. However, this weakness
is inherent in the assessment of any patient-reported outcome,
including HRQOL, and is not specic to our study. Fourth,
although our sample exceeds the usual 1020:1 ratio of subjects
to independent variables, it is nonetheless possible that we
might have overt the model on the basis of too few outcome
events. However, overtting is typically associated with unreal-
istically large estimated coefcients and/or standard errors. Our
point estimates for HRQOL and MELD are consistent with
those from other studies evaluating the association between
these scores and mortality in other areas of medicine and
advanced liver disease, respectively.
14,15,33
The fact that we and
others found similar effect sizes for the key predictors not only
provides convergent validity to these ndings but also suggests
that overtting might not be a signicant issue in our analysis.
Despite these corroborating data, future studies with larger
sample size and longer follow-up will be needed to conrm our
results. Moreover, because our goal was to determine whether
HRQOL could predict mortality independent of MELD score,
we did not seek to develop a predictive model that accurately
predicts mortality in cirrhosis. Future studies with character-
ization of the full spectrum of patient and non-patient factors
might allow a more accurate prediction of prognosis in patients
with cirrhosis.
In conclusion, our results demonstrate that a short, disease-
targeted HRQOL instrument can be used to identify patients
with advanced liver disease who are at high risk of short-term
death. These ndings provide additional support to the validity
of the SF-LDQOL as an HRQOL measure in patients with
advanced liver disease. HRQOL assessments might complement
objective measures of disease severity not only to accurately and
comprehensively assess health status but also to better risk
stratify patients with advanced liver disease. Our results under-
score the utility of HRQOL in patients with advanced liver
disease beyond its mere use as a secondary outcome in clinical
trials and observational studies.
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Reprint requests
Address requests for reprints to: Brennan M. R. Spiegel, MD, MSHS,
11301 Wilshire Boulevard, Building 115, Room 215, Los Angeles,
California 90073. e-mail: bspiegel@mednet.ucla.edu; fax: (310) 268-
4510.
Conicts of interest
The authors disclose no conicts.
Funding
Dr Kanwal is supported by Veterans Affairs Health Services Re-
search and Development (HSR&D) Investigator Initiated Research
Award IIR-07-111. Dr Spiegel is supported by a Veterans Affairs
Health Services Research and Development (HSR&D) Career Develop-
ment Transition Award (RCD 03-179-2) and by the CURE Digestive
Disease Research Center (NIH 2P30 DK 041301-17). Dr Hays is
supported by the UCLA Center for Health Improvement in Minority
Elderly/Resource Centers for Minority Aging Research, NIH/NIA/
NCMHD, under grant P30AG021684-07. This study was supported by
a Clinical Research Grant from the American College of Gastroenter-
ology.
The opinions and assertions contained herein are the sole views of
the authors and are not to be construed as ofcial or as reecting the
views of the Department of Veteran Affairs.
July 2009 HRQOL AND MORTALITY IN CIRRHOSIS 799