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Risk Factors for the Presence of Varices in Cirrhotic Patients Without a History of Variceal Hemorrhage
Atif Zaman, MD, MPH;
Thomas Becker, MD, PhD;
Jodi Lapidus, PhD;
Kent Benner, MD
Arch Intern Med. 2001;161:2564-2570.
ABSTRACT
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Background Current medical management dictates that all cirrhotic patients without
a history of variceal hemorrhage undergo endoscopic screening to detect large
varices. However, referral for endoscopic screening of only patients at highest
risk for varices may be most cost-effective. The aim of this case-control
study was to identify clinical, laboratory, and radiologic findings that predict
the presence of varices in patients with cirrhosis.
Methods Three hundred patients without a history of variceal hemorrhage underwent
upper endoscopy as part of an evaluation before liver transplantation. Cases
defined as the presence of any varices and cases defined as the presence of
large varices were used for examining the risks associated with finding varices
on upper endoscopy. Logistic regression was performed to evaluate associations
between the presence of varices and patient characteristics.
Results Platelet count and Child-Pugh class were independent risk factors for
the presence of any varices and the presence of large varices. For the presence
of any varices, a platelet count of 90 x 103/µL or
less (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.4-4.0) and advanced
Child-Pugh class (OR, 3.0; 95% CI, 1.6-5.6) were independent risk factors.
For large varices, a platelet count of 80 x 103/µL
or less (OR, 2.3; 95% CI, 1.4-3.9) and advanced Child-Pugh class (OR, 2.8;
95% CI, 1.3-5.8) were independent risk factors associated with varices.
Conclusions Low platelet count and advanced Child-Pugh class were associated with
the presence of any varices and with large varices. These factors allow identification
of a subgroup of cirrhotic patients who would benefit most from referral for
endoscopic screening for varices.
INTRODUCTION
CHRONIC LIVER disease is the 10th leading cause of death in adults in
the United States, accounting for approximately 25 000 deaths annually
(1% of all deaths).1 Cirrhosis is considered
the most advanced stage of chronic liver disease. Several complications are
related to advanced liver disease, including the development of variceal hemorrhage,
portosystemic encephalopathy, and ascites. Variceal hemorrhage is a consequence
of the development of portal hypertension, which is the most common and severe
complication in patients with cirrhosis of the liver. Portal hypertension
develops in cirrhosis because of an increase in splanchnic blood flow secondary
to vasodilation within the splanchnic vascular bed and because of increased
resistance to the passage of blood through the liver.2
After varices have developed, one third of all patients die of bleeding
gastroesophageal varices.3-4 The
risk of initial bleeding from varices is 25% to 35% in 2 years, with most
first-bleeding episodes occurring within a year of detection of varices.5-6 The reported mortality from a first
episode of variceal bleeding ranges from 17% to 57%.7
Of patients who survive the initial episode of bleeding and do not receive
active treatment ( -adrenergic blocking agents or endoscopy), two thirds
will have another episode of bleeding within 6 months of the initial episode.7-8 The current belief is that bleeding
from varices occurs when the wall of the varix ruptures, and the risk of rupture
is related to the wall tension of the varix. Therefore, large varices are
more likely to bleed than are small varices.5, 9
Studies by the Northern Italian Endoscopic Club5
and Zoli et al10 have shown that the frequency
of bleeding from large varices is 50% to 53% compared with 5% to 18% for small
varices. In addition, gastric varices also have a high frequency of bleeding
(approximately 25%).11
To alter these negative statistics, researchers have proposed numerous
medical and surgical approaches in the past 2 decades to reduce the incidence
of initial variceal bleeding. Portosystemic shunt surgery has been effective
in preventing first variceal hemorrhage, but it significantly increases the
risk of chronic or recurrent encephalopathy and reduces survival because of
perioperative complications.12-14
The clinical role of prophylactic endoscopic sclerotherapy and band ligation
remains unclear. In a recent meta-analysis,15
cirrhotic patients with large varices and no history of variceal hemorrhage
who were given -adrenergic blocking agents had less chance of variceal
bleeding (pooled odds ratio [OR], 0.48) and of dying of bleeding and experienced
a trend toward reduction in the total mortality rate compared with patients
not given -adrenergic blocking agents. Based on the results of these
studies, the American College of Gastroenterology recommends screening all
cirrhotic patients for the presence of esophageal varices and treating patients
with large varices with -adrenergic blocking agents to reduce the incidence
of first variceal bleeding.16 Other investigators17-18 recommend that screening be performed
every 2 years for cirrhotic patients without varices and that patients with
known small varices undergo endoscopy every year. However, these guidelines
have not been prospectively studied, and their cost-effectiveness has not
been demonstrated.
It may be more cost-effective to routinely screen only cirrhotic patients
at high risk for the presence of varices. Several studies5, 10, 19
have revealed factors that predict risk for first variceal hemorrhage, namely,
high Child-Pugh score, variceal size, signs of variceal wall thinning, presence
of gastric varices, presence of portal hypertensive gastropathy, and hepatic
vein pressure gradient. However, factors that predict the presence of varices
are not as well defined. The aim of this study was to identify patient characteristics—including
laboratory, radiologic, and physical examination findings—that predict
the presence of any varices and the presence of large esophageal varices by
using the Oregon Health Sciences University and Portland Veterans Administration
Medical Center (OHSU/PVAMC) liver transplantation database of patients with
advanced cirrhosis who routinely undergo screening endoscopy as a part of
their evaluation.
PARTICIPANTS, MATERIALS, AND METHODS
STUDY DESIGN
This was an unmatched case-control study, with cases and controls selected
from patients undergoing liver transplantation evaluation at the OHSU/PVAMC
Liver Transplantation Program between January 1, 1995, and September 1, 1999.
This study was approved by the institutional review board of Oregon Health
Sciences University, Portland. Patients were included in the study if they
had not had a history of variceal hemorrhage and were part of the OHSU/PVAMC
liver transplantation evaluation database. Two different case and control
definitions were used to examine possible risk factors. Initially, cases were
defined as cirrhotic patients diagnosed as having large varices on screening
upper endoscopy, and controls were cirrhotic patients with small or no varices
(these could be considered "clinical" controls because small varices are not
considered clinically significant). For the second analysis, cases were defined
as patients with any type of varices, and controls were cirrhotic patients
without varices ("true" controls).
DEFINITIONS
Screening endoscopies were performed by several endoscopists (A.Z.,
K.B., and others) who used different classifications to define variceal size.
In some cases, endoscopists used the grade (I-IV) classification.20 In other cases, endoscopists used the "small, medium,
or large" classification: small varices flatten with insufflation of the esophageal
lumen, medium varices do not flatten with insufflation, and large varices
do not flatten with insufflation and are confluent.17
Most endoscopists classified varices as either small or large (small varices
flatten with insufflation or minimally protrude into the lumen and large varices
protrude into the lumen and touch each other [presence of confluence] or fill  50%
of the lumen), as described by De Franchis et al.21
This simple classification is considered the preferred classification by a
recent consensus conference on portal hypertension held in Baveno, Italy.22 Therefore, when endoscopists used the small, medium,
or large classification, medium was reclassified as small; when grades I through
IV were used, grades I and II were reclassified as small and grades III and
IV were reclassified as large for this study. Gastric varices were classified
as either isolated fundic varices or gastroesophageal varices. Because any
type of gastric varix is considered a high-risk lesion for bleeding, patients
with these lesions were analyzed as cases; in this study, 9 patients had small
varices with associated gastric varices, and 4 patients had isolated gastric
varices. Analyses were performed with and without gastric varices included
in the study group, and no differences were noted in the findings. Therefore,
results that include gastric varices are presented. Cirrhosis was defined
histologically or by using a combination of laboratory, radiologic, and physical
examination findings, as in previous studies.5
The liver transplantation database is composed of all patients with
cirrhosis undergoing liver transplantation evaluation at OHSU/PVAMC. The database
includes physical examination findings, laboratory data, and abdominal ultrasound
findings at the time of transplantation evaluation. Because physical examination
results can vary from examiner to examiner, physical examination data were
abstracted only from examinations performed by the 2 transplantation surgeons.
Physical examinations were performed in standardized fashion per transplantation
evaluation protocol. This database has been maintained since 1991 and contains
information on approximately 1200 patients. The results from the first 98
patients in this cohort regarding risk factors predicting the presence of
esophagogastric varices were presented previously.23
This study presents the results from the entire cohort of liver transplantation
patients undergoing liver transplantation evaluation at the OHSU/PVAMC Liver
Transplant Department between January 1, 1995, and September 1, 1999. All
patients were free of gastrointestinal tract complaints, including bleeding;
none were taking nonsteroidal anti-inflammatory drugs, acid-suppressing drugs,
or -adrenergic blocking agents; and all were abstinent from alcohol
intake for at least 6 months. In addition to recording endoscopic findings,
the following data were collected: age, sex, cause of cirrhosis, Child-Pugh
class and score, and physical examination findings of splenomegaly, ascites
(described as none, nontense, or tense), encephalopathy, and spider angiomata.
Also, laboratory data (total bilirubin, aminotransferase, blood urea nitrogen,
creatinine, and albumin levels; prothrombin time; and platelet count) and
abdominal ultrasound findings (ascites and splenomegaly) were collected.
STATISTICAL ANALYSIS
Statistical analysis was performed using a software package (SPSS 9.0;
SPSS Inc, Chicago, Ill). The following model-building strategy was used. After
data collection was completed, the distribution of all independent variables
was explored. Histograms were generated, and transformations (log transformations,
square, square root, etc) were performed when appropriate to normalize the
distribution or to identify any natural breaks in the data to facilitate categorization
of the data. Then, univariate analysis using logistic regression was applied
to identify significant associations with the dependent variable. Transformed
and untransformed data were used in the analysis. All analyses were repeated
for the 2 case definitions described in the "Study Design" subsection. When
cases were defined as having either the presence of any varices or the presence
of large varices, binary logistic regression24
was performed. Any independent variables with associations of P .2 then underwent multivariate analysis by simply entering them
together using the forward conditional stepwise method and the backward conditional
stepwise method. A screening P = .2 was used based
on model-building strategies proposed by Hosmer and Lemeshow.24
The following cutoff points were used for the binary and ordinal logistic
regression stepwise methods: P = .05 for entry into
the model and P = .10 for removal from the model.
Ninety-five percent confidence intervals (CIs) were used in all analyses.
The "best" model for each case definition was based on the strength of the
model (Hosmer and Lemeshow goodness-of-fit test), its clinical utility, and
the biologic plausibility of the model. Any continuous variables included
in the final model were then categorized to improve ease of use. Cutoff points
were determined using receiver operating characteristic curves, which can
determine the "ideal" cutoff points for screening tests in an objective fashion
by determining the value that maximizes sensitivity and minimizes 1 -
specificity.25 After the main effects model
was generated, confounding factors (any factor that changed the OR of the
main effects variables by 10%) and interactions were addressed.
RESULTS
Between January 1, 1995, and September 1, 1999, 629 cirrhotic patients
underwent liver transplantation evaluation. Of these, 300 patients did not
have a history of variceal hemorrhage (the study group). All patients were
abstinent from alcohol intake for at least 6 months. Patient demographics
(overall and by endoscopic findings) are listed in Table 1. Most patients (69%) were men, with a mean ± SD age
of 49.0 ± 7.7 years. Only a few patients (2%) were undergoing any -adrenergic
blocking agent or long-acting nitrate therapy before endoscopy. Most patients
were in Child-Pugh class B (58%). Fifty-eight percent of patients referred
for transplantation had hepatitis C as one of the causes of their liver disease,
and 71% had hepatitis C, alcohol, or both as an etiologic factor. Physical
examination, laboratory, and radiologic findings are given in Table 2. The group without varices had a higher mean platelet count
(mean platelet count, 128 500/mm3) than the group with small
varices (mean platelet count, 107 800/mm3) and the group with
large or gastric varices (mean platelet count, 76 500/mm3).
Also, the group without varices had more patients without ascites and encephalopathy
than the other groups. Otherwise, the 3 groups had similar physical examination,
laboratory, and radiologic findings.
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Table 1. Demographics and Characteristics of Study Participants, Risk
Factors for Varices Study, 1999*
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Table 2. Physical Examination, Laboratory, and Radiologic Findings
of Study Participants, Risk Factors for Varices Study, 1999*
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RISK FACTORS FOR THE PRESENCE OF VARICES
The final model had a goodness-of-fit test with P = .61, incorporated only 2 variables, and included variables that
reflected not only hepatic function (Child-Pugh class) but also portal hypertension
(platelet count). To further simplify the model so that it could be easily
used in a clinical setting, platelet count was dichotomized using receiver
operating characteristic curves. The cutoff platelet count of 90 x 103/µL gave maximum sensitivity of 0.598 and minimum 1 - specificity
of 0.379.
With advancing Child-Pugh class, the percentage of patients with varices
increased: 29 (44%) of 66 patients in Child-Pugh class A, 129 (74%) of 174
in Child-Pugh class B, and 45 (75%) of 60 in Child-Pugh class C had varices.
Also, a significantly higher percentage of patients with platelet counts of
90 x 103/µL or less had varices than did patients with
platelet counts greater than 90 x 103/µL (78% vs 56%).
Diuretic use was the only confounding variable; it reduced the OR of
the Child-Pugh class by more than 10% when entered into the model. Interaction
between the risk factors was not observed. The final model, adjusted for diuretic
use, is given in Table 3. The
data suggest that having a platelet count of 90 x 103/µL
or less was associated with a nearly 2 -fold increase in the risk of
having varices on upper endoscopy (OR, 2.4; 95% CI, 1.4-4.0) and that Child-Pugh
class B or C was associated with a nearly 3-fold increase in the risk of having
varices compared with Child-Pugh class A (Child-Pugh class B: OR, 3.0; 95%
CI, 1.6-5.6; Child-Pugh class C: OR, 2.7; 95% CI, 1.2-6.1). Using this regression
model, the probability of the diagnosis of any varices can be estimated. A
cirrhotic patient with a platelet count of 90 x 103/µL
or less who is in Child-Pugh class A, B, or C will have a probability of 0.57,
0.81, or 0.82, respectively, of having any varices on upper endoscopy. On
the other hand, a cirrhotic patient with a platelet count greater than 90
x 103/µL who is in Child-Pugh class A, B, or C will
have a probability of 0.36, 0.65, or 0.66, respectively, of having any varices
on upper endoscopy.
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Table 3. Results of Binary Logistic Regression Analysis for Risk Factors
for the Presence of Varices, Adjusted for Confounders, Risk Factors for Varices
Study, 1999
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RISK FACTORS FOR THE PRESENCE OF LARGE VARICES
The final model had a goodness-of-fit test with P = .25, incorporated only 2 variables, and included variables that
reflected not only hepatic function (Child-Pugh class) but also portal hypertension
(platelet count). To further simplify the model for use in a clinical setting,
platelet count was categorized using receiver operating characteristic curves.
The cutoff platelet count of 80 x 103/µL gave maximum
sensitivity of 0.624 and minimum 1 – specificity of 0.326.
With advancing Child-Pugh class, the percentage of patients with large
varices increased: 10 (15%) of 66 patients in Child-Pugh class A, 68 (39%)
of 174 in Child-Pugh class B, and 17 (28%) of 60 in Child-Pugh class C had
large varices. Also, a significantly higher percentage of patients with platelet
counts of 80 x 103/µL or less had large varices than
did patients with platelet counts greater than 80 x 103/µL
(43% vs 22%) (Table 4).
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Table 4. Results of Binary Logistic Regression Analysis for Risk Factors
for the Presence of Large Varices, Risk Factors for Varices Study, 1999
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Confounding by the other variables was not observed. Also, interaction
between the main effects variables was not observed. When Child-Pugh class
was kept as a 3-category variable, Child-Pugh class C was not independently
associated with the presence of large varices (P
= .28). This may be because not enough patients were in Child-Pugh class C
in the study and fewer of them had large varices compared with patients in
Child-Pugh class B. Because of this, Child-Pugh class was further categorized
into a binary variable: Child-Pugh class A vs Child-Pugh class B or C, where
10 of 66 patients in Child-Pugh class A had large varices compared with 85
of 234 in Child-Pugh class B or C. The final model is given in Table 4. Similar to the model assessing for the presence of varices,
the data suggest that having a platelet count of 80 x 103/µL
or less is associated with a nearly 2-fold increase in the risk of
having large varices on upper endoscopy (OR, 2.3; 95% CI, 1.4-3.9) and that
being in Child-Pugh class B or C is associated with a nearly 3-fold increase
in the risk of having large varices compared with being in Child-Pugh class
A (Child-Pugh class B or C: OR, 2.8; 95% CI, 1.3-5.8). The probability of
finding large varices, using this regression model, can be estimated based
on the independent variables. A cirrhotic patient with a platelet count of
80 x 103/µL or less and in Child-Pugh class A or class
B or C will have a probability of 0.24 or 0.46, respectively, of having large
varices on upper endoscopy. A cirrhotic patient with a platelet count greater
than 80 x 103/µL and in Child-Pugh class A or class
B or C will have a probability of 0.12 or 0.27, respectively, of having large
varices on upper endoscopy.
COMMENT
The study findings suggest that low platelet count and advanced Child-Pugh
class are independent risk factors for the presence of not only large varices
but also of any varices in cirrhotic patients. Among clinical, laboratory,
and radiologic findings, only platelet count and Child-Pugh class were independent
risks. A platelet count of 90 x 103/µL or less was
associated with a nearly 2-fold increase in the risk of having any
varices on upper endoscopy, and being in Child-Pugh class B or C was associated
with a nearly 3-fold increase in the risk of having varices compared with
being in Child-Pugh class A. A platelet count of 80 x 103/µL
or less was associated with a nearly 2-fold increase in the risk of
having large varices on upper endoscopy, and being in Child-Pugh class B or
C was associated with a nearly 3-fold increase in the risk of having large
varices compared with being in Child-Pugh class A.
Probability estimates for the presence of any varices, based on platelet
count and Child-Pugh class, ranged from 0.36 if the patient was in Child-Pugh
class A and had a platelet count greater than 90 x 103/µL
to a probability of 0.82 if the patient was in Child-Pugh class C and had
a platelet count of 90 x 103/µL or less. The probability
estimates for the presence of large varices ranged from 0.12 if the patient
was in Child-Pugh class A and had a platelet count greater than 80 x
103/µL to a probability of 0.46 if the patient was in Child-Pugh
class B or C and had a platelet count of 80 x 103/µL
or less. This suggests that cirrhotic patients who are in Child-Pugh class
A and have a platelet count greater than 80 x 103/µL
may not benefit from screening because their probability of having large varices
on upper endoscopy is low.
Few studies have been performed to evaluate clinical, laboratory, and
radiologic factors that are strongly associated with the presence of varices.
Cales et al17 report that of 84 patients, 16
without varices (19%) and 35 with small varices (42%) developed large varices
during 16-month follow-up. In their study, multivariate analysis revealed
that initial size of varices and interval worsening of the Child-Pugh score
predicted the development of varices. In a logistic regression study by Garcia-Tsao
et al26 of 180 patients, the presence of spider
angiomata, a low albumin level, and a low platelet count were independent
risk factors for the presence of varices. Chalasani et al27
found that of 346 patients, the presence of splenomegaly on physical examination
(OR, 2.0; 95% CI, 1.1-3.8) and a platelet count less than 88 x 103/µL (OR, 1.6; 95% CI, 1.0-3.0) were independent risk factors
for the presence of large varices. Finally, in a study by Pilette et al,28 of 116 patients with cirrhosis, a low platelet count,
high prothrombin time, and the presence of spider angiomata were independent
risk factors for the presence of varices.
In the present study, as in previous studies, low platelet count and
advanced Child-Pugh class were risk factors for the presence of both any varices
and large varices. Child-Pugh class is a well-validated classification for
the degree of hepatic function in patients with cirrhosis. Because portal
hypertension is a consequence in part of the generalized vasodilation and
the hyperdynamic splanchnic and systemic circulatory state,2
the degree of hepatic function likely affects the development of portal hypertension
via humoral factors and, therefore, the development of varices. The association
of platelet count to the presence of varices is probably a reflection of the
degree of portal hypertension and possibly other factors. The cause of splenomegaly
in cirrhotic patients is likely owing to the hemodynamic changes associated
with portal hypertension.29 Historically, splenic
sequestration or antibody-mediated destruction of platelets have been believed
to be the cause of thrombocytopenia in patients with cirrhosis.30-31
However, recent studies have implicated reduced hepatic production of liver-derived
thrombocytopoietic growth factor thrombopoietin as a major factor for thrombocytopenia
in cirrhosis of the liver.32-33
This study has several potential limitations. We evaluated only liver
transplantation candidates. Therefore, the findings may not be generalizable
to all cirrhotic patients. Also, because the data were collected retrospectively,
misclassification of the outcome was possible. To minimize misclassification,
every effort was made to review the endoscopic reports and, when possible,
photographs of the findings. Furthermore, analysis was conducted not only
defining a case as the presence of large varices but also defining a case
as the presence of any varices (the presence of any varices is difficult to
misclassify). The same risk factors were identified for both case definitions,
suggesting that even when cases were defined as large varices, misclassification
was likely minimal. The only difference was a platelet count cutoff value
that was lower for detecting the presence of large varices (80 x 103/µL compared with 90 x 103/µL). This lower
platelet count cutoff value for large varices seems plausible because the
degree of thrombocytopenia seems to be associated with the degree of portal
hypertension and likely the size of varices. Bias related to exposure history
was minimized by the fact that all exposure data were gathered in a standardized
fashion based on the liver transplantation evaluation protocol. In addition,
several precautions were undertaken to limit data abstraction bias. Data abstraction
was performed by only one person (A.Z.) to minimize variability in medical
record abstraction. Endoscopic findings were collected on different days than
clinical and radiologic data, and the 2 sets of data were initially placed
in different databases to prevent the data abstractor from linking the independent
and dependent variables and potentially biasing the data abstraction procedure.
Finally, the data were directly recorded in an electronic database to reduce
transcription errors.
In conclusion, our data suggest that low platelet count and advanced
Child-Pugh class are independent risk factors for the presence of any varices
and for the presence of large varices. For the presence of any varices, cirrhotic
patients with platelet counts of 90 x 103/µL or less
are nearly 2 times more likely to have varices on upper endoscopy
than are patients with a platelet count greater than 90 x 103/µL;
patients in Child-Pugh class B or C are nearly 3 times more likely to have
varices on upper endoscopy than are patients in Child-Pugh class A. Similarly,
for the presence of large varices, cirrhotic patients with platelet counts
of 80 x 103/µL or less are nearly 2 times more
likely to have large varices on upper endoscopy than are patients with a platelet
count greater than 80 x 103/µL; patients in Child-Pugh
class B or C are nearly 3 times more likely to have large varices on upper
endoscopy than are those in Child-Pugh class A.
Probability estimates based on logistic regression models using these
risk factors can stratify patients into low- or high-risk groups for having
varices. Risk stratification based on these risk factors may help clinicians
identify patients who would most likely benefit from referral for screening
for gastroesophageal varices. These findings, including the validity of the
models, need to be verified with prospectively collected data. Also, cost-effectiveness
analysis should be performed to determine which strategy is best: screening
all cirrhotic patients vs screening only high-risk patients vs no screening.
AUTHOR INFORMATION
Accepted for publication April 9, 2001.
Corresponding author and reprints: Atif Zaman, MD, MPH, Division
of Gastroenterology and Hepatology, PV-310, Oregon Health Sciences University,
3181 Sam Jackson Park Rd, Portland, OR 97201 (e-mail: zamana{at}ohsu.edu).
From the Division of Gastroenterology and Hepatology, Department of
Medicine (Drs Zaman and Benner), and the Department of Public Health and Preventive
Medicine (Drs Zaman, Becker, and Lapidus), Oregon Health Sciences University,
Portland.
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