CLINICAL PREDICTORS OF BLEEDING FROM ESOPHAGEAL VARICES A

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					Phil J of Gastroenterology 2006; 2:103-111                                                   Limquiaco J , et al.


                     CLINICAL PREDICTORS OF BLEEDING
              FROM ESOPHAGEAL VARICES :A RETROSPECTIVE STUDY
Jenny Limquiaco, Eulenia R Nolasco Maria Lourdes O Daez, Venancio I Gloria, Ernesto O Domingo, Virgilio
  P Banez, Felix M Zano, Melflor A Atienza, Peter P Sy, E Labio, A ntonio C Comia, Mark Anthony A De
             Lusong, Jun Pilapil, Sherwin Feir, Elmer Cabanayan, Patricia Anne Prodigalidad
                                       Section of Gastroenterology
                                        UP-PGH Medical Center

Objectives: Bleeding from gastroesophageal varices is the most serious and life-threatening complication of
cirrhosis and accounts for 10% of all cases of bleeding from the upper GI tract. It is essential to identify and
treat those patients at highest risk because each episode of variceal hemorrhage carries a 20% to 30% risk of
death, and up to 70% of patients who do not receive treatment die within 1 year of the initial bleeding episode.
The aim of this study is to determine the clinical predictors of bleeding esophageal varices.
Methods: A case record review was done to all patients with esophageal varices admitted at Philippine General
Hospital between January 2003 to August 2005. Various clinical, biochemical and endoscopic criteria were
applied retrospectively to determine the predictors of esophageal bleeding.
Results: Among 128 patients with esophageal varices, 40% was due to HBV , 37 % was due to alcohol related
cirrhosis , 22% had Schistosomiasis, 2% had TB of the Liver, 2% had HCC per biopsy, 5% had both Hepatitis B
and alcohol, 3% had both Hepatitis B and Schistosomiasis and 2% had Cyrptogenic cirrhosis as etiologic factor
for their liver disease. The majority of patients were Child’s B with only 23% being Child-Pugh class C. The
mean arterial pressure on admission was 85(+/-10)mmHg, hemoglobin was 108(+/- 117)g/l, platelet count
148,730(+/- 93350)x109/l, protime 0.65(+/-0.16)% activity, INR of 1.40(+/- 0.32), albumin 24(+/- 6)g/l, AST
64(+/- 45)u/l, ALT 60(+/- 35)u/l, Total Bilirubin 66(+/- 130)umol/l and Creatinine of 104(+/- 72)umol/l.
Splenomegaly was reported on 40%, 51% had no ascites, 27% had mild ascites, 13% had moderate ascites and
9% had massive ascites. Majority of the population had Gr III esophageal varices, 35% had 3 columns
esophageal varices on endoscopy, 23% had concomitant gastric varices, 78% had portal gastropathy. Platelet
count, presence of red color sign, number of columns of esophageal varices, presence of portal gastropathy and
gastric varices on EGD showed a significant positive correlation with bleeding.
Conclusion: Thrombocytopenia, presence of encephalopathy and endoscopic findings large varices, presence of
red color sign, fundal varix and portal gastropathy are predictors of esophageal variceal bleeding. This
stratification may help clinicians identify cirrhotic patients who will need aggressive pharmacologic and
endoscopic intervention for variceal bleeding.
Category: Liver; Article: Cross Sectional; Key Words: clinical predictors of bleeding, esophageal varices,
thrombocytopenia, encephalopathy, red color sign, fundal varix, portal hypertensive gastropathy

INTRODUCTION
        BLEEDING from gastro-oesophageal varices is the most serious and life-threatening complication of
cirrhosis and accounts for 10% of all cases of bleeding from the upper GI tract. Approximately two thirds of
patients with decompensated cirrhosis and one third of those with compensated cirrhosis have varices at the
time of diagnosis. However, only about one third of cirrhotic patients will bleed from their varices which
accounts for 80-90% of bleeding episodes in these patients.1 Despite the advances in treatment of variceal
bleeding, mortality remains high at around 40%, being closely related to the severity of underlying liver disease
as assessed by Child’s class and impairment of renal function. 1
        For optimal management, it is important to identify and stratify patients at highest risk for variceal
bleeding. De novo varices develop annually in 5% to 15% of patients with cirrhosis. Once present, varices


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Phil J of Gastroenterology 2006; 2:103-111                                                       Limquiaco J , et al.


enlarge by 4% to 10% each year. It is essential to identify and treat those patients at highest risk because each
episode of variceal hemorrhage carries a 20% to 30% risk of death, with 70% of patients not receiving treatment
will die within 1 year of the initial bleeding episode.2 Clinical factors associated with an increased risk of a first
variceal hemorrhage include continued alcohol use and poor liver function. Endoscopic predictors of bleeding
include endoscopic red signs on the variceal wall and large varices. 3 Cales et al stated that bleeding risk varied
according to variceal size. It is also positively correlated with plasma creatinine and negatively correlated with
age and mean arterial pressure.4 The prognostic influence of various patient characteristics on risk of bleeding
and death was also investigated by Moller et al .On univariate analysis , high plasma volume , high azygos
blood flow , high hepatic venous pressure gradient , marked prominence of varices on endoscopy, poor
nutritional status , low serum albumin , high bilirubin , high alkaline phosphatases , low arterial oxygen
saturation and encephalopathy showed a significant correlation with an increased risk of bleeding or death.5
Presence of tense ascites was also noted to be an independent predictor of variceal hemorrhage as stated in a
study done by Nidegger et al. On the contrary, neither ascites nor encephalopathy was correlated with variceal
bleeding in a study made by Kleber. 6
        Several studies have been published stating that thrombocytopenia, ascites and splenomegaly are useful
non invasive markers of large esophageal varices in cirrhosis and one paper came up recently using these non
invasive parameters to predict bleeding from esophageal varices. However, those parameters did not show a
significant correlation with hemorrhage.10 The role of coagulopathy and thrombocytopenia in the outcome of
acute variceal bleeding, and their therapeutic correction or amelioration have not been evaluated sufficiently.
Correlation of variceal bleeding and altered haemostasis has been scanty.8 Given these background and the high
mortality and substantial utilization of resources associated with the occurrence of variceal bleeding in patients
with cirrhosis, our aim is to focus on identifying which of the previously studied variables could predict
occurrence of hemorrhage from esophageal varices in a local setting. We also hope to discuss on the different
etiology of cirrhosis in the local setting and how it differs from the Western population.

GENERAL OBJECTIVE:
To be able to identify the clinical predictors of bleeding from esophageal varices admitted at PGH.

SPECIFIC OBJECTIVES:
   1. To describe the demographic profile of patients with liver cirrhosis and esophageal varices admitted at
      PGH from January 2003 to August 2005.
   2. To identify the clinical, biochemical ,endoscopic and ultrasonographic parameters which may predict the
      risk of bleeding from esophageal varices as follows:
          a. Clinical
                        • mean arterial pressure
                        • splenomegaly
                        • ascites
                        • Encephalopathy
          b. Biochemical parameters
                  • Platelet count
                  • Hemoglobin
                  • Hematocrit
                  • Creatinine
                  • Prothrombin time
                  • Albumin



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Phil J of Gastroenterology 2006; 2:103-111                                                   Limquiaco J , et al.


                   •   Bilirubin

           c. Abdominal ultrasound findings
                     portal vein diameter/flow
                     splenomegaly
                     ascites

MATERIALS AND METHODS:
        Medical records of patients with a clinical diagnosis liver cirrhosis who underwent endoscopy at
Philippine General Hospital between January 2003 to August 2005 were retrieved from the medical records
section. This list was cross-checked with the outpatient clinic charts for adequacy of data retrieval. Patients
were divided into 2 groups. Group A consisted of patients with a history and clinical presentation of bleeding
esophageal varices and Group B were those patients with esophageal varices on endoscopy but with no history
of variceal bleeding. The diagnosis of cirrhosis was based on a combination of clinical, laboratory and
radiographic criteria. Bleeding esophageal varices is defined as those patients who presented with upper
gastrointestinal bleeding manifested by hematemesis, melena and/or hematochezia with endoscopic
confirmation of esophageal variceal bleeding and no other bleeding lesion seen on endoscopy. Patients with a
clinical diagnosis of upper gastrointestinal bleeding due to acquired coagulopathy , gastric ulcers, duodenal
ulcers or gastric varices were excluded. Case records of eligible patients were reviewed to obtain the necessary
demographic, clinical, laboratory and endoscopic data. Esophageal varices were graded according to Japanese
Research for Portal Hypertension Classification System as follows: Gr I : small esophageal varices which
flatten with insufflation or minimally protrude into the esophageal lumen, Gr II: moderated sized varices with
minimal obscuring of the gastroesophageal junction, Gr III: large varices showing luminal proplapse
substantially obscuring the gastroesophageal junction and Gr IV: very large esophageal varices completely
obscuring the gastroesophageal junction and do not flattens on insufflation. The number of variceal columns,
presence of red color sign, presence of gastric varices and portal gastropathy were also recorded. Continuous
variables included age, hemoglobin, hematocrit, platelet count, serum creatinine, AST and ALT, albumin,
bilirubin, and prothrombin time expressed in percent activity and international normalized ratio. The categorical
variables included sex, etiology of liver disease, encephalopathy, ascites and splenomegaly based on physical
examination and/or ultrasonography.

STATISTICAL ANALYSIS:
      Data were analyzed utilizing the STATA SOFTWARE. Continuous variables were expressed as
means±standard deviation and nominal variables were recorded as frequencies. Student's unpaired t test or
Mann–Whitney test were used to compare continuous variables. The Chi2 test was used to identify differences
between categorical variables. P values less than 0.05 was considered to indicate statistical significance.

RESULTS
       From January 2003 to August 2005, retrospective data were collected on 128 liver cirrhotic patients who
underwent endoscopy. Ninety three (93) patients with esophageal variceal hemorrhage made up the study group
and thirty five (35) patients with esophageal varices but no history of variceal hemorrhage comprised the
negative control group. Patients with previous portosystemic shunts, with upper gastrointestinal bleeding but no
documented endoscopy or bleeding coming from sources other than esophageal varices were excluded from the
study. The demographic profile of the 2 groups are listed in Table 1. Forty (40%) had Hepatitis B , 37 % had
alcohol, , 22% had Schistosomiasis, 2% had TB of the Liver, 2% had HCC per biopsy, 5% had both Hepatitis B
and alcohol, 3% had both Hepatitis B and Schistosomiasis and 2% had Cyrptogenic cirrhosis as etiologic


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Phil J of Gastroenterology 2006; 2:103-111                                                   Limquiaco J , et al.


factors for their liver disease. Male compromised 71% of the study population with a mean age of 49 years. The
majority of patients were Child’s B with only 23% being Child-Pugh class C. Physical examination, laboratory,
and radiological findings are listed in Table 2. The mean arterial pressure on admission was 85(63-110)mmHg,
hemoglobin was 108(+/- 117)g/l, platelet count 148,730(+/- 93350)x10 9/l, protime 0.65(+/-0.16)% activity,
INR of 1.40(+/- 0.32), albumin 24(+/- 6)g/l, AST 64(+/- 45)umol/l, ALT 60(+/- 35)umol/l, TBil 66(+/-
130)umol/l and Creatinine of 104(+/- 72)umol/l. Splenomegaly was reported on 40%, 51% had no ascites, 27%
had mild, 13% had moderate ascites and 9% had massive ascites. Endoscopic findings are listed in Table3.
Majority of the population had Gr III EV, 35% had 3 columns EV on endoscopy, 23% had concomitant gastric
varices, 78% had portal gastropathy. Associated EGD findings were presence of duodenal ulcer, duodenitis and
gastric ulcers.
        On univariate analysis, only platelet count, hemoglobin (0.009) on admission, encephalopathy (0.043),
presence of red color sign(<0.001), number of columns of EV(<0.001), presence of portal gastropathy (<0.001)
and gastric varices(0.005) were significantly correlated with increased risk of bleeding from esophageal varices.


Table 1. Patient Demographics
             Characteristics                                    Data
Total number of patients                                         128
Male/Female                                                     91/37
Mean Age (year)                                            49(range: 19-79)
Etiology of liver disease
  Hepatitis B                                                  51(40%)
  Alcohol                                                      47(37%)
  Schistosomiasis                                              28(22%)
  Alcohol+Hepatitis B                                           6(5%)
  Hepatitis B+Schistosomiasis                                   4(3%)
  Hepatocellular CA                                             3(2%)
  TB of the Liver                                               3(2%)
  Cryptogenic                                                   2(2%)
Child-Pugh Classification (Score)
  A(5-6)                                                        4(3%)
  B(7-9)                                                       94(73%)
  C(10-15)                                                     30(23%)

Table 2. Physical Examination, Laboratory and Radiological Findings
                Findings                             Mean ( Range )
PHYSICAL EXAMINATION
Mean Arterial Pressure                               85(+/-10mmHg)
Ascites
   • None                                                64(51%)
   • Mild                                                34(27%)
   • Moderate                                            17(13%)
   • Massive                                             12(9%)
Splenomegaly                                             51(40%)
Encephalopathy


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Phil J of Gastroenterology 2006; 2:103-111                                    Limquiaco J , et al.


   • None                                          106(83%)
   • I                                             19(15%)
   • II                                             1(1%)
   • III                                            1(1%)
   • IV                                             0(0%)
LABORATORY DATA(mean+/-SD)
Hemoglobin g/l                                    108(+/- 117)
Platelet Count x 10 9/l                        148,730(+/- 93350)
Protime
   • % Activity                                  0.65(+/-0.16)
   • INR                                         1.40(+/- 0.32)
AST u/l                                            64(+/- 45)
ALT ul                                             60(+/- 35)
TB umol/l                                         66(+/- 130)
Albumin g/l                                         24(+/- 6)
Creatinine umol/l                                 104(+/- 72)

Table 3: Endoscopic Findings
                Findings                            N (%)
Esophageal Varices
Grade
   • I                                             22(17%)
   • II                                            33(26%)
   • III                                           70(55%)
   • IV                                             3(2%)
Column
   • 1                                              7(5%)
   • 2                                             34(27%)
   • 3                                             45(35%)
   • 4                                             42(33%)
Red Whale Sign
   • Positive                                      91(71%)
   • Negative                                      37(29%)
Gastric Varices                                     29(23%)
Portal Gastropathy                                 100(78%)
Other Associated EGD findings
   • Duodenal Ulcer                                 2(2%)
   • Duodenitis                                     1(1%)
   • Gastric Ulcer                                  1(1%)

Table 4: Univariate Analysis
        Characteristics                Grp A    Grp B               P value
Male/Female                            68/25    23/12                0.410


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Phil J of Gastroenterology 2006; 2:103-111                                        Limquiaco J , et al.


Mean Age (year)                       47(+/- 1.3)      52(+/- 2.2)      0.108
Etiology of liver disease
  Alcohol                             34(37%)           13(37%)         0.951
  Hepatitis B                         38(41%)           13(37%)         0.702
  Schistosomiasis                     21(23%)            7(20%)         0.753
  TB of the Liver                      2(2%)              2(2%)         0.620
  Hepatocellular CA                    1(2%)              2(6%)         0.181
  Alcohol+Hepatitis B                  6(6%)              0(0%)         0.188
  HepatitisB + Schistosomiasis         4(4%)              0(0%)         0.576
  Cryptogenic                          1(1%)              1(3%)         0.474
Child’s Pugh Turcotte score
  A(5-6)                                2(2%)             2(6%)
  B(7-9)                               66(71%)          28(80%)         0.219
  C(10-15)                             25(27%)           5(14%)

Table 4. Univariate Analysis
       Findings                  Grp A                   Grp B          P value
PHYSICAL EXAMINATION
Ascites
   • None                      46(50%)                  18(52%)
   • Mild                      25(27%)                  9(26%)
   • Moderate                   13(14%)                 4(11%)           0.965
   • Massive                     8(9%)                  4(11%)
Splenomegaly                   39(42%)                  12(34%)          0.431
Encephalopathy
   • None                      72(78%)                  34(97%)
   • I                          18(20%)                  1(3%)
   • II                          1(1%)                   0(0%)           0.043
   • III                         1(1%)                   0(0%)
   • IV                          0(0%)                   0(0%)
LABORATORY DATA(mean+/-SD)
Hemoglobin g/l                  90(+/- 22)             (152(+/- 21)      0.009
Platelet Count x10 9/l    122570(+/- 55666)         218231(+/- 22237)    0.000
Protime
   • % Activity              0.65(+/- 0.15)           0.67(+/- 0.17)     0.438
   • INR                     1.38(+/- 0.32)           1.46(+/- 0.35)     0.226
AST u/l                       65(+/- 50%)               64(+/- 32)       0.953
ALT u/l                        58(+/- 35)               63(+/- 38)       0.619)
TB umol/l                     59(+/- 132)              79(+/- 129)       0.558
Albumin g/l                    23(+/- 5.8)              25(+/- 6.5)      0.184
Creatinine umol/l             101(+/- 68)              114(+/- 83)       0.476


Table 4: Univariate Analysis


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Phil J of Gastroenterology 2006; 2:103-111                                                        Limquiaco J , et al.


                Findings                            Grp A           Grp B           P value
Grade of Esophageal Varices
   • I                                              2(2%)          20(57%)
   • II                                            21(23%)         12(34%)         0.000
   • III                                           67(72%)          3(9%)
   • IV                                             3(3%)           0(0%)
No. of Columns
   • 1                                             1(1%)            6(17%)
   • 2                                            17(18%)          17(49%)         0.000
   • 3                                            38(41%)          7(20%)
   • 4                                            37(40%)          5(14%)
Red Whale Sign                                    91(98%)            0(0%)           0.000
Gastric Varices                                   27(29%)            2(6%)           0.005
Portal Gastropathy                                82(88%)          18(51%)           0.000

DISCUSSION:
        Variceal hemorrhage is associated with significant morbidity, mortality, and health care cost in patients
with liver cirrhosis. With endoscopic assessment and follow up, the prevalence of esophageal varices has been
reported to be as high as 80-90%. Up to 30 percent of initial bleeding episodes are fatal, and as many as 70
percent of survivors have recurrent bleeding after the first variceal hemorrhage.3
        In this retrospective study of patients with cirrhosis, the etiology of liver cirrhosis varies with that in the
western population. It was found out that Hepatitis B 51(40%) is the leading cause of liver cirrhosis with
Alcoholism 47(37%) comes second to Hepatitis B .This is true owing to the high prevalence(8-15%) of HBV
infection in the Southeast Asian nation. These findings were consistent with the local study done by Parreno et
al.15 Being a country endemic in Schistosomiasis, a considerable percentage (22%) of the population had
esophageal varices secondary to hepatosplenic Schistosomiasis. This results in intrahepatic presinusoidal portal
hypertension with resultant esophageal and gastric varices which carries an important cause of morbidity and
mortality. Over the course of time, Schistosoma induced presinusoidal portal hypertension usually progresses
and may generate a more complex and mixed pattern of vascular resistance leading to cirrhosis. Cirrhosis will
also develop in hepatosplenic schistosomiasis if co-infected with viral hepatitis which is evident in 2% of the
study population. Furthermore, the combination of chronic schistosomiasis caused by S. mansoni and HBV
infection may result in a higher risk of hepatocellular carcinoma than that attributable to HBV alone.13 There is
therefore a need for increased support for schistosomiasis control in addition to environmental and behavioral
modification.
        Endoscopy proved to be a powerful tool for the determination of bleeding risks. Higher grade
esophageal varices, red color sign, portal gastropathy and presence of fundal varices are other predictors of
bleeding in esophageal varices. The red color sign corresponds to the dilated blood-filled channels lying within
and beneath the squamous epithelium. A high variceal blood pressure might be involved in the pathogenesis of
the lesion. The bleeding incidence is increased to 4.7 fold in the presence of cherry red spots or red whale
markings.16 It confirms the 3 previous trials on the evaluation of red color sign in predicting bleeding from
esophageal varices.
        Another significant endoscopic predictor of bleeding from esophageal varices noted in this study is the
size of the varix. Variceal size is one of the factor that contributes to wall tension. A large varix will reach a
high wall tension and risk of bleeding at lower variceal pressure than a small varix with thick walls. Prospective



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Phil J of Gastroenterology 2006; 2:103-111                                                       Limquiaco J , et al.


studies of large series of patients have shown that the risk of bleeding is directly related to the size and inversely
related to variceal wall thickness.
        In addition, the presence of concomitant gastric varices could be added as a further criterion for the
prediction of bleeding from esophageal varices. To date, there are no prospective studies reported locally on the
bleeding incidence in patients with concomitant gastric varices. In our study, the presence of gastric varices in
predicting bleeding from esophageal varices is noteworthy. Close anatomical connections have been
demonstrated between the veins of the stomach and the distal esophagus. Furthermore, the presence of the
varices in the gastric fundus indicates a particularly high venous blood pressure in that area thus offering an
explanation for the increased bleeding risk.17 These findings were similar to the prospective studies done by
Kleber.
        Another criterion in predicting bleeding from esophageal varices is the presence of portal gastropathy on
endoscopy. Prevalence of hypertensive gastropathy parallels the severity of portal hypertension and liver
dysfunction. A high portal pressure (>12mmHg) can explain the snake skin appearance of gastric mucosa on
endoscopy and positively correlates with the risk of bleeding.
        Thrombocytopenia is the laboratory feature which is positively correlated with bleeding. Low platelet
count can be explained by hypersplenism involved in the disease process. In the presence of portal hypertension,
as much as 90% of the circulating thrombocytes are sequestered in the spleen, leading to a significant reduction
in the circulating platelet count. In alcohol-related liver disease, ethanol may directly suppress platelet
production, and folate deficiency, a common finding in advanced liver disease, further impairs production.18
         However, Child’s Pugh Turcotte score, ascites and splenomegaly failed to show a positive correlation
with bleeding. Being a tertiary hospital, most patients referred to our institution are with relatively advanced
disease. Majority of the patients on both groups belonged to CPT Class B. Being a retrospective study, variables
needed to satisfy Child’s-Pugh score were not complete in all patients. Tendency to underestimate Child’s status
in the study group could also be a possibility. In one retrospective study done by Nidegger et al, presence of
tense ascites was an independent predictor of variceal hemorrhage but 2 more studies performed a prospective
evaluation of ascites proved a contradictory outcome.6,10 It is noted that although intra- abdominal pressure
clearly influences several hemodynamic variables in portal hypertension, there is no convincing evidence that
tense ascites per se, increases risk of variceal bleeding.19
        As this was a retrospective study, it is difficult to standardize the reporting of the endoscopic findings. In
the course of reviewing medical charts of the patients, some charts did not contain a complete report of
biochemical tests to satisfy Child’s Classification parameters. Some were not requested, others were not done
due to financial constraints, while a number were due to inadequate record keeping. Perhaps, an updated
detailed description of EGD findings should be implemented to standardize interpretation. Another possible
way to improve it is to supply photographs of the EGD findings to increase the likelihood of a uniform
interpretation. A database data collection is thereby recommended to gain trouble-free and complete access of
patient’s medical profile and facts and ensure adequacy of data retrieval.
        Since platelet count is positively correlated with bleeding, cutoff values providing the best sensitivity
and specificity for the outcomes of interest should be identified and validated in another set of similar patients.
This can be achieved by constructing a RECEIVER OPERATOR CHARACTERISTIC (ROC) curves and
plotting sensitivity and specificity for continuous variables.

CONCLUSION:
        Thrombocytopenia, presence of encephalopathy, low hemoglobin on admission, and endoscopic
findings large varices, presence of red color sign, fundal varix and portal gastropathy are predictors of
esophageal variceal bleeding. This stratification may help clinicians identify cirrhotic patients who will need
aggressive pharmacologic and endoscopic intervention for variceal bleeding.


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Phil J of Gastroenterology 2006; 2:103-111                                                Limquiaco J , et al.


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