Cover

Prospective study on the

development and complications

of variceal bleeding in patients

with liver cirrhosis

2 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis

Contents

INTRODUCTION 13

PRESENT KNOWLEDGE IN LITERATURE

1. Pathophysiology data of liver cirrhosis 17

1.1. Portal hypertension in liver cirrhosis 17

1.2. Pathophysiological features of upper variceal gastrointestinal

bleeding in cirrhotic patients 19

2. Treatment principles of variceal bleeding in cirrhotic patients 23

2.1. Concepts of primary prophylaxis of variceal bleeding in cirrhotic patients.

The role of endoscopic therapy in primary prevention 23

2.1.1. Primary prevention strategy of variceal bleeding by

pharmacological means 24

2.1.2. The role of endoscopic therapy in the primary prevention

of variceal bleeding 25

2.2. Specific treatment (hemostasis) of active variceal bleeding 26

2.2.1. Treatment with vasoactive pharmacological agents of active

variceal bleeding 26

2.2.2. Endoscopic treatment of active variceal bleeding 26

2.3. Concepts of secondary prophylaxis of variceal bleeding 28

3. Complications of variceal bleeding in cirrhotic patients 31

3.1. Complications associated with variceal bleeding 31

3.1.1. Hepatic encephalopathy 31

3.1.2. Bacterial infections 32

3.1.3. Hepato-renal syndrome 33

3.1.4. Bleeding relapses 34

3.1.5. Hypovolemic shock 34

3.1.6. Variceal bleeding consequences on cardiovascular diseases 35

3.1.7. Complications due to pharmacotherapy and to therapeutic

procedures in variceal bleeding 36

ORIGINAL PART

1. Hypothesis / objectives 41

2. Study 1. The etiopathogenesis of the upper gastrointestinal bleeding

in cirrhotic patients and the variceal bleeding risk factors 43

2.1. Introduction 43

2.2. Objectives 43

2.3. Materials and methods 43

2.3.1. Study group 43

2.3.2. Variables 45

Anca Romcea 3

2.3.3. Statistical analysis 46

2.4. Results 47

2.4.1. Aspects of pathogenesis of the upper gastrointestinal bleeding in

cirrhotic patients 49

2.4.2. Aspects of risk factors of variceal bleeding in cirrhotic patients 58

2.5. Discussions 67

2.6. Conclusions 69

3. Study 2. Evolution and complications of the variceal bleeding in cirrhotic

patients 71

3.1. Introduction 71

3.2. Objectives 72

3.3. Materials and methods 72

3.3.1. Study group 72

3.3.2. Variables 75

3.3.3 Statistical analysis 75

3.4. Results 76

3.4.1. Aspects of the first bleeding relapse 78

3.4.2. Implications of the drug and endoscopic treatment in relapses

of variceal bleeding in cirrhotic patients. 85

3.4.3. Complications in relapses of variceal bleeding in cirrhotic patients 88

3.4.4. Analysis of mortality in variceal bleeding 92

3.4.5. Prediction factors of survival after variceal bleeding 97

3.5. Discussions 103

3.6. Conclusions 105

4. General conclusions 107

5. Originality and innovative contributions of the thesis 111

REFERENCES 113

4 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis

Keywords:

variceal bleeding, esophageal varices, upper gastrointestinal bleeding in cirrhotic

patients, variceal bleeding risk factors, endoscopic treatment for variceal

bleeding, mortality in variceal bleeding.

Introduction

The upper gastrointestinal bleeding in cirrhotic patients is one of the

major pathology problems of Gastroenterology and it is also a public health

issue with high incidence, severe complications and high costs involved in giving

the required health care to these patients.

In spite of the application of preventive measures, as well as despite the

improvement of diagnostic methods and the greater efficiency of treatment

methods, liver cirrhosis with its most feared complication - the upper

gastrointestinal bleeding - remains a major public health problem.

The upper gastrointestinal bleeding in cirrhotic patients mainly occurs

because of esophageal and gastric varices. However, there are a significant

number of non-variceal bleeding cases too. Therefore, the first study aimed to

analyze the etiopathogenesis of the upper gastrointestinal bleeding in patients

with liver cirrhosis and to assess the risk factors involved in the occurrence of

variceal bleeding. The study included 900 patients with cirrhosis, which allowed

us to have an overview of the upper gastrointestinal bleeding in cirrhotic patients.

After the first episode of variceal bleeding, the risk for a bleeding relapse is

high, whereas complications (hepatic and extrahepatic ones) and mortality may

be due to multiple factors: the severity of bleeding (ie hemodynamic imbalance),

worsening of the liver failure (assessed by the Child-Pugh criteria), the

association of other diseases (infections, diabetes mellitus, heart disease,

hepatocellular carcinoma, etc.). Moreover, the methods of treatment applied to

the patients, when they experience the first variceal bleeding, involve a change in

the frequency of relapses, in the timing of their occurrence in relation to the initial

bleeding episode and in the long-term survival.

The second study looked into the bleeding relapses that occurred in patients

after the first variceal bleeding episode. Moreover, we studied the risk factors for the

first bleeding relapse, the influence of medication and that of the endoscopic

Anca Romcea 5

treatment, the complications and the mortality issues. We also analyzed the

prediction factors of survival at one year of the initial bleeding episode. International

guidelines contain a number of recommendations including an essential one, namely:

the indication to perform the upper gastrointestinal endoscopy within the first 24

hours in all patients with upper gastrointestinal bleeding.

In our country, according to the data from the Romanian Society of

Endoscopy, there are few medical centers in which on duty permanent endoscopy

service exists, and in many of the units in which emergency upper gastrointestinal

endoscopy is performed during office hours there are no resources required for

performing endoscopic hemostasis. In this respect, in order to complete the

present thesis, due to the existing on duty service, we benefited from the

possibility of performing upper gastrointestinal endoscopy in all the patients who

presented with an episode of bleeding, in the "Prof. O. Fodor" Regional Institute of

Gastroenterology and Hepatology. Moreover, all the patients received endoscopic

treatment conducted by experienced endoscopy specialists.

Hypothesis/ Objectives

The causes of upper gastrointestinal bleeding (UGI bleeding) may be

variceal or non-variceal, hence the importance of performing the upper

gastrointestinal endoscopy within the first 24 hours of admission of the UGI

bleeding patient. Thus, the source of bleeding can be specified and the

appropriate endoscopic treatment initiated.

The life prognosis of a patient with variceal upper gastrointestinal

bleeding depends on the severity of the haemorrhage, on the hepatic functional

reserve (cirrhosis stage), on the degree and location of the varices (esophageal or

gastric), on the patient’s age, on the existence of associated diseases, on the

specific treatment, etc.

For this reason, we decided to monitor the etiopathogenesis of upper

gastrointestinal bleeding in cirrhotic patients, the risk factors for variceal

bleeding, its severity, the efficiency of the endoscopic hemostasis techniques, the

assessment of bleeding relapses, the mortality and survival of these patients.

Numerous published studies have shown correlations between certain

clinical, biochemical and ultrasound parameters and the risk for variceal bleeding,

with variable results. Therefore, our first study, in this thesis, looked into some of

these aspects and into what causes variceal bleeding in these patients.

6 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis

The results of speciality studies cannot be extrapolated directly onto the

cases in the territory as the variceal bleeding risk factors can significantly vary

depending on the population’s genetics, on environmental conditions and on

socio-economic conditions. This is the reason why, we considered the present

doctoral thesis useful.

Study 1. The etiopathogenesis of upper gastrointestinal bleeding in

cirrhotic patients and the variceal bleeding risk factors

Objectives

The objectives of the study were to analyze the etiology of non-variceal

bleeding in cirrhotic patients and the risk factors for variceal bleeding.

Materials and methods

The study group

The study was an analytical, experimental, longitudinal and prospective

type of study conducted in the period 1.11.2004-31.05.2006, in the "Prof. O.Fodor

" Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca.

Data collection was conducted by sampling, the patients study group

consisting of a representative sample.

The general group included 938 patients diagnosed with liver cirrhosis

according to clinical, biochemical, ultrasonographic and endoscopic criteria,

whereas the documentation was completed from the patients’ observation

charts. Out of the 938 patients, the group of study interest included 217 patients

with UGI bleeding, who underwent upper gastrointestinal endoscopy for

diagnosis and treatment, under emergency conditions, in the Digestive

Endoscopy Office of the"Prof. Dr. O.Fodor" Regional Institute of

Gastroenterology and Hepatology, Cluj-Napoca.

The study group of patients with bleeding was divided into two

subgroups: the group of patients with variceal bleeding (N = 168) and the group

of patients with non-variceal bleeding (N = 49). The control group consisted of

patients with no bleeding (N = 721). The patients who had upper

gastrointestinal bleeding from gastric varices were excluded from the study.

Anca Romcea 7

After the variceal or non-variceal source of the UGI bleeding was identified,

endoscopic therapy was applied where necessary.

In the cases of variceal bleeding, endoscopic sclerotherapy was

performed by using hypertonic glucose solution or by inserting elastic ligatures

according to possibilities, under emergency conditions; in the cases of non-

variceal bleeding, adrenaline 1/10000 and absolute alcohol were injected or

metal clips were inserted, depending on the etiology of the bleeding.

A record chart, which included the following data, was completed for each

patient, upon inclusion in the study:

personal data (name, age, gender)

personal pathological history suggestive of the underlying disease and of

comorbidities (liver virus infections, alcohol consumption, autoimmune

diseases, diabetes mellitus, HCC, etc.)

complete diagnosis (the underlying disease, associated diseases),

classification according to the Child-Pugh criteria

symptoms and signs:

- type of bleeding (hematemesis, melena, hematochezia)

- severity of the bleeding

- ascites

- jaundice

- the degree of hepatic encephalopathy (I, II, III, IV)

laboratory findings: complete blood count, INR, bilirubin, transaminases,

etc.

upper GI endoscopy - signaling the presence of esophageal and / or

gastric varices, the presence / absence of active bleeding on examination,

with or without signs of recent bleeding (clots), varices grade (I, II, III),

the presence / absence of red signs on the esophageal varices according

to the Guide of the Japanese Society of Endoscopy, the presence of other

bleeding lesions (ulcers, gastritis, angiodysplasia, portal hypertensive

gastropathy, polyps, Mallory-Weiss syndrome - MWS, esophagitis, etc.)

abdominal ultrasound- spleen, VP size, presence / absence of ascites, of

HCC

infections - respiratory infections, urinary infections, spontaneous

bacterial peritonitis

endoscopic treatment- sclerotherapy, elastic ligatures, injection of

adrenaline, absolute alcohol, metal clips insertion, argon plasma

coagulation (APC)

patient’s drug therapy -propranolol, nitrates.

8 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis

The patient’s record chart contains clinical and laboratory data recorded

on admission, during hospitalization and at hospital discharge.

The study was approved by the local ethics committee of "Prof. O. Fodor"

Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca.

Results

Out of the 938 patients included in the study, 217 patients had upper

gastrointestinal bleeding (168 variceal bleeding cases and 49 non-variceal cases).

The variceal bleeding was the dominant etiology, accounting for 77.42% of the

upper gastrointestinal bleeding in the cirrhotic patients included in the study.

Non-variceal bleeding occurred at a rate of 22.58% of the upper gastrointestinal

bleeding. Peptic ulcer caused 12.44% of the initial episodes of UGI bleeding,

Mallory-Weiss syndrome caused 3.68%, acute erosive gastritis 1.84%, portal

hypertensive gastropathy 1.38% and the remaining 3.22% were bleeding from

the esophageal ulcer, gastric angiodysplasia, antral vascular ectasia, duodenal

polyps and gastric tumors.

Comparing the two groups of patients, those with variceal bleeding (N =

168) and the non-variceal bleeding ones (N = 49), in terms of the incidence of

bleeding depending on the cirrhosis severity, a statistically significant association

was found between the Child-Pugh class and the type of bleeding. Thus, there is a

higher occurrence of variceal bleeding in the patients from Child-Pugh class B (74

patients) and C (57 patients), compared with non-variceal bleeding that occurred

more frequently in patients from Child-Pugh A and B, ie the non-variceal bleeding

risk was 2.5 times higher in patients from Child-Pugh class A and B than in those

from the Child-Pugh class C (p = 0.008, Chi Square test, oR = 2.5, 95% CI 1.2 to 5.2).

The Mallory-Weiss syndrome shows a statistically significant association (p =

0.041) with ethanolic etiology, male gender (p = 0.02, RR = 1.35, 95% CI 1.1-1.6), with

the simultaneous presence of gastric varices on the upper gastrointestinal endoscopy

(p <0.001, RR = 13.34, 95% CI 3.2 to 55.58) in these patients, the Child-Pugh class A

cirrhosis (p = 0.045, RR = 4, 95% CI 2.1 to 17.87). As to the portal hypertensive

gastropathy, there is an association with thrombocytopenia (plt <60000) (p =

<0.001), INR> 2 (p = 0.001) and the Child-Pugh class C (p = <0.001). The bleeding

episode was more severe in the group with variceal bleeding than in that of non-

variceal bleeding (p <0.001, Chi-square test). The risk for the hemorrhagic

episode to be more severe in the variceal bleeding patients is 1.6 times higher

than in the non-variceal bleeding patients (RR = 1.6, 95% CI 1.28 to 2.01). Severe

bleeding was present in 69.59% of the patients who had upper gastrointestinal

Anca Romcea 9

bleeding. The variceal intrusion is the main source of bleeding in severe bleeding

(87.42%), whereas peptic ulcer and the Mallory-Weiss syndrome are mainly

diagnosed in moderate and mild bleeding (71.4%). To analyze the risk factors for

variceal bleeding in cirrhotic patients, we studied 168 patients with variceal

bleeding, in comparison with the control group, which included 721 patients

without bleeding (variceal or non-variceal). The variceal bleeding was the

dominant etiology, accounting for 77.42% of the upper gastrointestinal bleeding

in the cirrhotic patients included in the study. In the study group, the ethanolic

etiology of liver cirrhosis as a risk factor (p <0.001, RR = 1.63, 95% CI: 1.26 to

2.10) for variceal bleeding stood out, while the C viral etiology was found to be a

protective factor (p <0.001, RR = 0.64, 95% CI: 0.48 to 0.86). No other etiology

was found to be statistically significant (B viral liver cirrhosis with p = 0.587, p =

0.36 autoimmune cirrhosis, etc.).

It was determined that there is an acceptable association (φc = 0.33, p

<0.001) between the Child-Pugh class and the occurrence of variceal bleeding

(Cramer's V coefficient). The Child-Pugh class A is a protective factor , while the

Child-Pugh class C is a risk factor (p <0.001, RR = 2.39) for the occurrence of

variceal bleeding in the cirrhotic patients from the study group. The esophageal

varices intrusion depends on the grade of the varicose veins, being more frequent

in patients with grade II and III varices (p <0.001), while the risk for bleeding

from varices grade III is 3.7 times higher than in patients with varicose veins

grade I and II. On the upper digestive endoscopy, the highlighting of red marks on

the surface of esophageal varices and the simultaneous presence of gastric varices

were found to be in a statistically significant correlation (p <0.001, RR = 7) using

Chi-Square test, with the risk of bleeding from esophageal varices. The platelet

count <60,000 / mm3 was recorded in 57 patients with variceal bleeding. This

was found to be a statistically significant association with the increased risk for

variceal bleeding in these patients (RR = 1.83, 95% CI: 1.41 to 2.37, p <0.001). The

hepatic encephalopathy was also associated with the risk for variceal bleeding in

the cirrhotic patients from our study (RR = 1.45, 95% CI: 1.19 to 1.76, p <0.001). It

was determined that the spleen diameter > 140mm counted as a risk factor in the

occurrence of variceal bleeding (RR = 1.78, 95% CI: 1.35 to 2.34, p <0.001).

In our study, spontaneous bacterial peritonitis was found to be in a

statistically significant association with the risk for variceal bleeding (RR = 1.75, p

<0.003), respiratory infections were correlated with p <0.003 and RR = 1.78,

while urinary infections increased the risk for variceal bleeding (p = 0.03) by 1.38

times. Patients with variceal bleeding associated with PBS were patients with

advanced liver cirrhosis.

10 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis

The presence of HCC was found in 10.12% of the patients with variceal

bleeding and it was highlighted as a risk factor for variceal bleeding (RR = 1.1; 95%

CI: 0.72 to 1.65). However, it was not found to be statistically significantly

associated with the variceal bleeding (p = 0.68). To determine the diagnostic value

of certain numeric parameters (patient’s age, the longitudinal diameter of the

spleen, platelet count, the portal vein diameter) the ROC curves (Receiver Operating

Characteristic) were constructed and compared. The ROC curve graphically

illustrates the relationship between sensitivity and specificity for certain possible

cut-off values. The optimal values in terms of reliability of the analyzed parameters

are considered cut-off points. The cut-off value (the point where sensitivity and

specificity are at a maximum) determined with highly statistical significance (p

<0.001) for the platelet count is 138,500 / mm3. For this threshold, the specificity is

high, i.e. 83.6%, which means that the variceal bleeding is well-diagnosed. Thus, a

positive result confirms the diagnosis of variceal bleeding, but the sensitivity is

reduced. The longitudinal diameter of the spleen, measured by ultrasound, was

established to have a threshold value of 232.5 mm (p <0.001) with high specificity,

but very low sensitivity. For the portal vein diameter, a cut-off value of 9.6 mm (p

<0.001) was fixed, with very high sensitivity (98.3%), which means that a negative

result (below the threshold) refutes the diagnosis of variceal bleeding. Age shows a

cut-off of 54.5 years, but without statistical significance (p = 0.245).

Study 2. Evolution and complications of variceal bleeding in cirrhosis

Objectives

The objectives of the study were to evaluate the evolution of variceal

bleeding, the aspects of bleeding relapse, the implications of the treatment

principles, the complications within bleeding relapses and the factors predictive

of survival in the patients included in the study.

Materials and methods

The study group

The study was one of an analytical, experimental, longitudinal,

prospective type, conducted in the period 1.11.2004-31.08.2006. The

Anca Romcea 11

inclusion and study of patients within regular check-ups took place at "Prof.

Fodor O. " Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca,

for over a year, until 31.08.2007. Data collection was conducted by sampling

and the study group consisted of a representative patient sample. The study

included 198 patients, with upper gastrointestinal bleeding from esophageal

varices, who underwent diagnostic and therapeutic upper gastrointestinal

endoscopy, under emergency conditions, at the Office of "Prof. O.Fodor"

Regional Institute Endoscopy Gastroenterology and Hepatology Cluj-Napoca.

The study included only patients whose source of bleeding was the esophageal

varices intrusion. This was assessed by emergency endoscopic examination

performed within 6 hours of the patient’s admission at the latest.

Subsequently, we studied 74 patients who had variceal bleeding relapses while

the control group was formed of patients without bleeding relapses (N = 124).

Patients, who had a diagnosis of cirrhosis of unknown etiology at the time of

discharge, were excluded from the study. After the source of variceal bleeding

in the UGI bleeding had been identified, endoscopic therapy was performed

(elastic ligatures or sclerotherapy with hypertonic glucose solution, depending

on the specific possibilities). In order to investigate the factors predictive of

morbidity and mortality after bleeding episodes, as well as those predictive of

survival, we monitored bleeding relapses because of esophageal varices

intrusion, the occurrence or worsening of specific complications of cirrhosis -

hepatic encephalopathy, spontaneous bacterial peritonitis, ascites, the

occurrence or worsening of complications due to associated diseases

(infections, cardiovascular diseases, etc.), the number and causes of deaths.

Regular check-ups were carried out after 6 weeks, 3 months, 6 months and 1

year of the initial bleeding.

The study was stopped for each patient at the end of the follow-up

period or in case of death. The study was approved by the local ethics

committee of "Prof. O. Fodor" Regional Institute of Gastroenterology and

Hepatology, Cluj-Napoca.

Results

Out of the 198 patients with variceal bleeding, bleeding relapses occurred

in 74 patients: 48 men and 26 women. In the group of patients with bleeding

relapses, there were a total of 118 bleeding relapses in the period immediately

after the application of endoscopic hemostasis, (between 2 and 5 bleeding

episodes per patient).

12 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis

Out of the 198 cases in which control over the initial variceal bleeding was

obtained, the first hemorrhagic relapse was recorded in 37.37% of the patients.

Gender, age and etiology of cirrhosis of patients who experienced variceal bleeding

did not correlate with the risk for a first bleeding relapse. There is a statistically

significant correlation of the first bleeding relapse with the Child-Pugh liver cirrhosis

(p = 0.04); mainly patients with liver cirrhosis of Child-Pugh class B (37.6%) and C

(44%) presented a bleeding relapse, in comparison with patients in Child-Pugh class

A who had their first variceal bleeding (23%). The severity of the acute bleeding

episode originally influences the occurrence of the relapse (p <0.001). Thus, out of the

54 patients with a clinically significant bleeding episode when they first had variceal

bleeding, 30 patients had their first hemorrhagic relapse.

Prevention of bleeding relapses, by pharmacological treatment, was done by

administering beta-blockers. Monitoring the response to treatment could ideally

be done by GVPH measuring, but this was dependent on the access to methodology

and on the generated costs. Thus, decision was made to decrease the pulse by 25%

of the baseline. Each patient in the group of patients with variceal bleeding was

administered 20-80 mg of propranolol, starting on the sixth day of hospital

admission for the first variceal bleeding episode. The influence of the beta-blocker

administration on the occurrence of bleeding relapses was presented previously.

We continued to study the influence of the treatment with nonselective beta-

blockers (propranolol), nitrates or combinations of the two classes of drugs, on all

the 118 bleeding relapses occurred in the group of 74 patients.

• Analysis of variceal bleeding mortality

During the first variceal bleeding and during bleeding relapses 47 deaths

were recorded.

The following factors were found to statistically significantly correlate

with mortality within the first 48 hours:

- severity of cirrhosis: deaths were recorded, within the first 48 hours, only in

cases with Child-Pugh class B and C liver cirrhosis; no death was recorded in

the Child-Pugh class A (p = 0.04).

- severity of bleeding: we have noticed an increased death rate at 48 hours in

cases with clinically significant bleeding (p <0.001).

- HCC presence - increased the risk of death at 48 hours by 4 times in these

patients; 33.33% of the deceased patients at 48 hours also had HCC

(p = 0.004, RR = 4, 95% CI: 1.5 - 10.63).

Anca Romcea 13

- large amount of ascites - correlates with death at 48 hours (p = 0.017).

Gender and the age of patients, the etiology of cirrhosis and the endoscopic

treatment were not found to have significantly correlated with the deaths

recorded within 48 hours after the initial bleeding, but we found that 33.3% of the

patients who died in this period were diagnosed with liver cirrhosis of alcohol

consumption etiology (p = 0.05).

In the following period, from day 3 and up to six weeks after the initial

bleeding episode, 40.43% of all deaths in the study group were recorded and they

mainly occurred because of hemorrhagic shock (Fig. 17) .

The analysis of mortality up to 6 weeks showed statistically significant

correlation with the following factors:

- Child-Pugh C liver cirrhosis - in the deceased patients compared with the

cirrhosis severity in the patients who survived (p = 0.015, RR = 2.5, 95% CI:

1.4 to 12.7)

- treatment with medication - no treatment with propranolol was correlated

with death (p <0.001, RR = 1.33, 95% CI: 1.1-1.6); patients who did not

receive beta-blockers had a risk of death by 1.33 times higher than those who

were treated with medication.

- treatment performed endoscopically - of all deaths up to 6 weeks, there was

no death in patients with associated endoscopic treatment (sclerotherapy

and ligation); 79% of deaths occurred in patients treated by endoscopic

sclerotherapy of esophageal varices (p = 0.002)

- -presence of HCC - increased the risk of death in these patients by 4.5 (p

<0.001, RR = 4.5, 95% CI: 1.97 to 10.32)

- associated PBS increased the risk of death by 2.35, at 6 weeks (p = 0.048, RR

= 2.35, 95% CI: 1.1 to 5.7)

- hepatic encephalopathy was present in 73.7% of the patients who died up

until 6 weeks (p = 0.001) in comparison with the survivors

- acute ischemic hepatitis increased the risk of death by 12.5 (p = 0.031, RR =

12.5, 95% CI: 1.05 to 5.89)

- hemorrhagic shock increased the risk of death in these patients by 5.94 (p

<0.001, RR = 5.94, 95% CI: 2.5 to 14.1)

Mortality between 46 and 365 days, after the initial bleeding episode, was

found to have a statistically significant correlation with the presence of HCC (p

<0.001, RR = 6.18, 95% CI: 2.26 to 16.91) in the deceased patients (13 patients) in

comparison with the survivors (151 patients), and with the presence of

hemorrhagic shock (p <0.04, RR = 2.91, 95% CI: 1.02 to 8.25).

14 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis

• Prediction factors of survival after variceal bleeding

At the end of one year since the first bleeding episode, 47 patients died and

151 survived. After the initial episode of variceal bleeding, patients were given

medication (propranolol, nitrates or propranolol plus nitrates) and were called

for check-ups to undergo consolidation therapy for the esophageal varices by

sclerotherapy or elastic ligatures.

• General conclusions

UGI bleeding occurred in 23.14% of the cirrhotic patients included in the

study, the variceal bleeding representing the dominant etiology and accounting

for 77.42% of the first episode of bleeding in these patients.

Non-variceal bleeding occurred in 22.58% of all the patients with upper

gastrointestinal bleeding and was represented, in descending order, by: peptic

ulcer, Mallory-Weiss syndrome, acute erosive gastritis, portal hypertensive

gastropathy and other etiologies which were seldom found in our study

(esophageal ulcer, gastric angiodysplasia, antral vascular ectasia, duodenal polyps

and gastric tumors).

The incidence of UGI bleeding was high in patients aged over 55 years, the

gender ratio male:female being 2:1 in both groups of patients (both in the variceal

bleeding goup and in the non-variceal bleeding group).

Alcoholic etiology was predominant in the variceal bleeding group.

Non-variceal upper gastrointestinal bleeding such as those of peptic ulcer

type, acute erosive gastritis and esophageal ulcer were recorded in greater

numbers in patients with Child-Pugh class A and B liver cirrhosis, in comparison

to those with Child-Pugh class C liver cirrhosis.

Mallory-Weiss syndrome shows a statistically significant correlation with

ethanolic etiology, male gender and Child-Pugh class A.

portal hypertensive gastropathy bleeding was found in correlation with

thrombocytopenia (plt <60,000), INR> 2 and Child-Pugh class C cirrhosis.

Comparing the two groups of patients (the variceal bleeding group vs.

the non-variceal bleeding group), the risk for non-variceal bleeding was 2.5

times higher in patients with Child-Pugh class A and B than in patients with

Child-Pugh class C.

Anca Romcea 15

The bleeding episode was more severe in the group with variceal bleeding

than in the non-variceal bleeding group.

The variceal intrusion was the main bleeding source in severe bleeding;

peptic ulcer and Mallory-Weiss syndrome were mainly diagnosed in moderate

and mild bleeding.

The esophageal varices intrusion depended on the varices grade, on the presence

of variceal red wheals and it increased with the severity of the liver damage.

The presence of hepatic encephalopathy, platelet count <60,000 / mm3 and

the spleen longitudinal diameter>140 mm were found to have a statistically

significant correlation with the risk of variceal bleeding.

Bacterial infections - spontaneous bacterial peritonitis, respiratory infections,

and urinary tract infections occurred in 49.4% of the patients in the group with

variceal bleeding.

The presence of HCC was found in 10.12% of the patients with variceal

bleeding, but did not correlate with the risk of variceal bleeding.

Building and comparing ROC curves for the group of patients with variceal

bleeding, a threshold of 138,500 / mm3 for the platelet count was set and of 232.5

mm for the longitudinal spleen diameter to make the diagnosis of variceal

bleeding. The size of the portal vein was set below 9.6 mm in order to refute

variceal bleeding. However, none of these parameters had a big enough AUC to

make a firm diagnosis.

By multivariate logistic regression it was found that the strongest predictor

of variceal bleeding was the presence of red weals on the surface of esophageal

varices, followed by the ethanol etiology of cirrhosis, Child-Pugh class C,

thrombocytopenia below 138,500 / mm3 and the grade of the esophageal

varices, the latter highlighting a directly proportional relationship between a

higher grade of the esophageal varices and the influence on the occurrence of

variceal haemorrhage.

The risk for the first bleeding relapse in cirrhotic patients increased with

the severity of the liver disease (Child-Pugh class), with the presence of

hemorrhagic shock and of acute alcoholic hepatitis during the first episode of

variceal bleeding.

The drug treatment with propranolol as secondary prophylaxis is a

protection factor for the first bleeding relapse; the endoscopic sclerotherapy

treatment resulted in a higher incidence of the first bleeding relapse than that

performed with elastic ligatures.

In all the bleeding relapses that occurred in the cirrhotic patients from our

study, no treatment with propranolol statistically significantly correlated with the

16 Prospective study on the development and complications of variceal bleeding in patients with liver cirrhosis

occurrence of bleeding relapse, while the endoscopic ligation treatment of the

esophageal varices correlated with a decrease in relapse episodes.

Bleeding complications that occurred during relapses were found to have a

statistically significant correlation with the severity of cirrhosis, the presence of

hemorrhagic shock and the hepatic encephalopathy.

Bacterial infections (spontaneous bacterial peritonitis, respiratory and

urinary tract infections) were common in the first bleeding relapse and were

present in 41.2% of these patients.

Overall mortality by variceal bleeding was 23.73%.

The causes of death were: hemorrhagic shock (47%), hepatic coma (38%),

myocardial infarction (13%) and stroke (2%).

Immediate mortality, within the first 48 hours after the initial bleeding

episode, was statistically significantly correlated with the severity of the liver

cirrhosis, with the presence of hemorrhagic shock, with a large amount of ascites,

with serum bilirubin> 3 mg / dl, with acute ischemic hepatitis, with HCC, with

myocardial infarction and spontaneous bacterial peritonitis in these patients.

Mortality within 3 days to 45 days (six weeks) of the initial bleeding episode

significantly correlated with Child-Pugh class C cirrhosis, with no treatment with

propranolol, with the endoscopic sclerotherapy treatment versus ligation or

combined therapy, with HCC, with the spontaneous bacterial peritonitis, with the

hepatic encephalopathy, with the hemorrhagic shock and acute ischemic hepatitis

in patients who died, in comparison with the survivors from our study.

From 46 days up until one year after the initial bleeding episode, mortality

was recorded in 6.56% of the patients and our study found it statistically

significantly correlated with the presence of HCC and the hemorrhagic shock.

The statistical analysis of the events recorded after one year from the first

episode of variceal bleeding in the cirrhotic patients from our study revealed that

the patients who survived longer were patients with Child-Pugh class A liver

cirrhosis, without PBS, who were given drug treatment with propranolol and

whose esophageal varices were treated by sclerotherapy plus elastic ligatures;

these patients had no hemorrhagic shock during the acute episode and were aged

under 55 years. The most important survival prognostic factors analyzed by

multivariate Cox regression were: the hemorrhagic shock, PBS, the treatment with

propranolol and the applied endoscopic treatment.