Anca Romcea -Teza de Doctorat (Rezumat EN)

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

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

Contents INTRODUCTION PRESENT KNOWLEDGE IN LITERATURE 1. Pathophysiology data of liver cirrhosis 1.1. Portal hypertension in liver cirrhosis 1.2. Pathophysiological features of upper variceal gastrointestinal bleeding in cirrhotic patients 2. Treatment principles of variceal bleeding in cirrhotic patients 2.1. Concepts of primary prophylaxis of variceal bleeding in cirrhotic patients.

The role of endoscopic therapy in primary prevention 2.1.1. Primary prevention strategy of variceal bleeding by pharmacological means 2.1.2. The role of endoscopic therapy in the primary prevention of variceal bleeding 2.2. Specific treatment (hemostasis) of active variceal bleeding 2.2.1. Treatment with vasoactive pharmacological agents of active variceal bleeding 2.2.2. Endoscopic treatment of active variceal bleeding 2.3. Concepts of secondary prophylaxis of variceal bleeding 3. Complications of variceal bleeding in cirrhotic patients 3.1. Complications associated with variceal bleeding 3.1.1. Hepatic encephalopathy 3.1.2. Bacterial infections 3.1.3. Hepato-renal syndrome 3.1.4. Bleeding relapses 3.1.5. Hypovolemic shock 3.1.6. Variceal bleeding consequences on cardiovascular diseases 3.1.7. Complications due to pharmacotherapy and to therapeutic procedures in variceal bleeding ORIGINAL PART 1. Hypothesis / objectives 2. Study 1. The etiopathogenesis of the upper gastrointestinal bleeding in cirrhotic patients and the variceal bleeding risk factors 2.1. Introduction 2.2. Objectives 2.3. Materials and methods 2.3.1. Study group 2.3.2. Variables

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2.3.3. Statistical analysis 2.4. Results 2.4.1. Aspects of pathogenesis of the upper gastrointestinal bleeding in cirrhotic patients 2.4.2. Aspects of risk factors of variceal bleeding in cirrhotic patients 2.5. Discussions 2.6. Conclusions 3. Study 2. Evolution and complications of the variceal bleeding in cirrhotic patients 3.1. Introduction 3.2. Objectives 3.3. Materials and methods 3.3.1. Study group 3.3.2. Variables 3.3.3 Statistical analysis 3.4. Results 3.4.1. Aspects of the first bleeding relapse 3.4.2. Implications of the drug and endoscopic treatment in relapses of variceal bleeding in cirrhotic patients.

3.4.3. Complications in relapses of variceal bleeding in cirrhotic patients 3.4.4. Analysis of mortality in variceal bleeding 3.4.5. Prediction factors of survival after variceal bleeding 3.5. Discussions 3.6. Conclusions 4. General conclusions 5. Originality and innovative contributions of the thesis REFERENCES

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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

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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.

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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.

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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 nonvariceal 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.

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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 nonvariceal 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

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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 (Ď&#x2020;c = 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.

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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 (patientâ&#x20AC;&#x2122;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

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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 patientâ&#x20AC;&#x2122;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).

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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 betablockers (propranolol), nitrates or combinations of the two classes of drugs, on all the 118 bleeding relapses occurred in the group of 74 patients.

â&#x20AC;˘ 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).

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- 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).

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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.

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 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

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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.