الفهرس 
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Abstract
Liver cirrhosis is a chronic irreversible liver disease. Portal hypertension is a frequent complication of liver cirrhosis. Esophageal varices (EV) are frequently seen in patients with liver cirrhosis. Variceal bleeding is the most lethal complication of liver cirrhosis and portal hypertension.
Several vasoactive molecules regulate the vascular tone in both the liver microcirculation and the systemic and splanchnic circulations. Nitric oxide (NO), a vasodilator, is an important member of these molecules. Increased systemic and splanchnic levels of NO metabolites and diminished their effect in the hepatic circulation have been shown to play a key role in the pathogenesis of portal hypertension.
Various polymorphisms of the eNOS gene have been suggested to influence eNOS expression and NO circulating levels. A polymorphism in the eNOS gene, consisting of four or five repeats of a 43-base-pair sequence, has been described. So, three genotypes can be identified: 5/5, 4/5, and 4/4. Although EV are commonly seen among patients with cirrhosis, a number of patients do not develop this complication. Genetic variation at the eNOS gene could be implicated in this observation.
The aim of this work was to study relationship between:
1) eNOS gene polymorphism and serum level of NO metabolites in patients with liver cirrhosis.
2) eNOS gene polymorphism and degree of portal hypertension, development of esophageal varices, and risk of bleeding in these patients.
The study was carried out on 75 patients with liver cirrhosis and 50 healthy control subjects. They were divided into 3 groups:
Group I: included 50 cirrhotic patients with esophageal varices, gastric varices, and/or portal hypertensive gastropathy. This group was subdivided into two subgroups:
Subgroup A: included 25 patients with history of upper gastrointestinal bleeding (hematemesis and/or melena).
Subgroup B: included 25 patients without history of upper gastrointestinal bleeding.
Group II: included 25 cirrhotic patients without esophageal varices, gastric varices, and/or portal hypertensive gastropathy.
Group III: included 50 healthy control subjects of matched age and sex with the patients groups.
Patients with portal hypertension due to other causes than liver cirrhosis, and those with portal vein thrombosis, hepatocellular carcinoma, or history of surgical intervention for portal hypertension were excluded from the study.
Patients with cardiovascular, pulmonary, endocrinal, or renal diseases were excluded to avoid hemodynamic changes resulting from these diseases. Also, patients treated with nitrates or beta blockers were excluded.
The diagnosis of liver cirrhosis was based on clinical, biochemical, and ultrasonographic data.
All subjects were subjected to the following:
1) Detailed history taking.
2) Thorough clinical examination.
3) Laboratory investigations including: urine and stool analysis particularly for schistosoma ova, complete blood count, blood urea, serum creatinine, fasting blood glucose, serum alanine transaminase, serum aspartate transaminase, serum bilirubin, serum albumin, prothrombin activity, serum HCV antibodies, HBV surface antigen, indirect hemagglutination test for schistosomiasis, and serum alpha feto protein.
All patients were classified and scored according to modified Child-Pugh criteria.
4) Electrocardiogram and X-ray chest.
5) Serum nitrite/nitrate levels as an index of NO synthesis.
6) Detection of eNOS genotype using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) technique (for the eNOS 4/5 (intron 4) polymorphism).
7) Ultrasound abdomen and Doppler study of the portal venous system for the patients groups using a 3.5 mHz sector transducer scanner and pulsed flowmetry.
8) Upper gastrointestinal endoscopy was done for the cirrhotic patients using a video-endoscopy Olympus XQ 240.
The results of this study showed the following:
1. There was no statistically significant difference regarding age & sex between cirrhotic patients with and without EV, and between cirrhotic patients having EV with and without history of variceal bleeding.
2. The number of patients with jaundice, splenomegaly, and anterior abdominal wall collaterals were significantly higher in cirrhotic patients with EV than in cirrhotic patients without EV, but no statistically significant difference was found regarding these variables between cirrhotic patients with & without history of bleeding EV. All other clinical variables studied showed no statistically significant difference between cirrhotic patients with and without EV, or between cirrhotic patients with and without history of bleeding EV.
3. Hemoglobin level and platelets count were significantly lower in cirrhotic patients with EV than in cirrhotic patients without EV, and in cirrhotic patients with history of bleeding EV than in cirrhotic patients without history of bleeding EV. No statistically significant difference was found between cirrhotic patients with and without EV, or between cirrhotic patients with and without history of bleeding EV regarding WBCs count, blood urea, serum creatinine, and fasting blood glucose.
4. Serum bilirubin level was significantly higher in cirrhotic patients with EV than in cirrhotic patients without EV, and in cirrhotic patients with history of bleeding EV than in cirrhotic patients without history of bleeding EV. Serum albumin level and prothrombin activity were significantly lower in cirrhotic patients with EV than in cirrhotic patients without EV, but no statistically significant difference was found between cirrhotic patients with and without history of bleeding EV.
5. There was no statistically significant difference between cirrhotic patients with and without EV, or between cirrhotic patients with and without history of bleeding EV regarding serum AST level, serum ALT level, and AFP level.
6. There was no statistically significant difference between cirrhotic patients with and without EV regarding Child-Turcotte-Pugh class. The class was significantly advanced in cirrhotic patients with history of bleeding EV than in cirrhotic patients without history of bleeding EV.
7. There was no statistically significant difference between cirrhotic patients with and without EV, or between cirrhotic patients with and without history of bleeding EV regarding HCV & HBV markers and IHA test results.
8. Longitudinal diameter of the spleen, portal vein (PV) diameter, splenic vein (SV) diameter, superior mesenteric vein (SMV) diameter, portal vein cross sectional area, portal vein flow volume (PFV), portal vein congestion index (PCI), and percentage of patients with hepatofugal portal blood flow were significantly higher, while portal vein mean velocity (PMV) was significantly lower in cirrhotic patients with EV than in cirrhotic patients without EV, and in cirrhotic patients with history of bleeding EV than in cirrhotic patients without history of bleeding EV.
9. There was no statistically significant difference between cirrhotic patients with and without EV, or between cirrhotic patients with and without history of bleeding EV regarding longitudinal diameter of the Rt. hepatic lobe or grade of PPF.
10. Presence of collaterals was significantly higher in cirrhotic patients with EV than in cirrhotic patients without EV, but not significantly higher in cirrhotic patients with history of bleeding EV than in cirrhotic patients without history of bleeding EV.
11. Degree of ascites was significantly more advanced in cirrhotic patients with history of bleeding EV than in cirrhotic patients without history of bleeding EV, but this was not found between cirrhotic patients with and without EV.
12. Red spot score, NIEC index, NIEC class, and estimated risk of bleeding were significantly higher in cirrhotic patients with history of bleeding EV than in cirrhotic patients without history of bleeding EV.
13. Size of EV, grade of GV, and degree of PHG showed no statistically significant difference between cirrhotic patients with and without history of bleeding EV.
14. Serum nitrite level was significantly higher in cirrhotic patients than in healthy control subjects, in cirrhotic patients with EV than in cirrhotic patients without EV, and in cirrhotic patients with history of bleeding EV than in cirrhotic patients without history of bleeding EV.
15. The same results were found regarding serum nitrate level, except that, there was no statistically significant difference between cirrhotic patients without EV and healthy control subjects.
16. Also, serum nitrite and nitrate levels correlated with the grade of EV and with risk of its bleeding.
17. There was no statistically significant difference between cirrhotic patients and healthy control subjects regarding eNOS genotypes. Genotype 5/5 was detected significantly more in cirrhotic patients with EV than in cirrhotic patients without EV, and in cirrhotic patients with history of bleeding EV than in cirrhotic patients without history of bleeding EV.
18. Regarding portal hemodynamics, only PCI was found to be significantly higher in cirrhotic patients of genotype 5/5 than in cirrhotic patients of genotypes 4/4 & 4/5, and in cirrhotic patients having EV of genotype 5/5 than in cirrhotic patients having EV of genotype 4/4.
19. Serum nitrite/nitrate levels were significantly higher in subjects of genotype 5/5 than in subjects of genotypes 4/4 & 4/5. In cirrhotic patients, serum nitrite/nitrate levels were significantly higher in cirrhotic patients of genotype 5/5 than in cirrhotic patients of genotypes 4/4 & 4/5, and in cirrhotic patients of genotype 4/5 than in cirrhotic patients of genotype 4/4.
20. Grade of EV was significantly higher in cirrhotic patients of genotype 5/5 than in cirrhotic patients of genotypes 4/4 & 4/5. Red spot score was significantly higher in cirrhotic patients of genotype 5/5 than in cirrhotic patients of genotypes 4/4 & 4/5, and in cirrhotic patients of genotype 4/5 than in cirrhotic patients of genotype 4/4.
21. Grade of GV was significantly higher in cirrhotic patients of genotype 5/5 than in cirrhotic patients of genotypes 4/4 & 4/5.
22. Degree of PHG was significantly higher in cirrhotic patients of genotype 5/5 than in cirrhotic patients of genotype 4/4.
23. Risk of EV bleeding was significantly higher in cirrhotic patients of genotype 5/5 than in cirrhotic patients of genotypes 4/4 & 4/5.