Clinical Observation On Risk Factors Of Cirrhotic Patients With Esophageal Variceal Bleeding And Preliminary Study On Relationship Between Hemorrhage And Gene Polymorphism Of Catechol-O-methyltransferase

Background Esophageal variceal bleeding, a major complication of portal hypertension resulting from cirrhosis, accounts for 10 to 30 percent of all cases of bleeding from the upper gastrointestinal tract.Variceal hemorrhage is associated with more than 30 percent of high mortality, and the rebleeding rate is also high.Therefore, evaluating the risk factors of bleeding before esophageal variceal hemorrhage using the clinical presentations needs further analysis for larger samples. As we know that plasma concentrations of catecholamines are very high in patients with cirrhosis. Catecholamines including norepinephrine and epinephrine participated in the systemic and visceral haemodynamics disturbance, which promotes esophageal variceal bleeding. Catechol-O-methyltransferase (COMT) inactivates catecholamines and a common genetic polymorphism in humans is associated with a three-to-four-fold variation in COMT enzyme activity due to G→A transition at the COMT gene that results in a valine to methionine substitution, which shows clinical significance. The relationships between the COMT gene polymorphism and the susceptibility to cirrhotic patients with portal hypertension as well as the risk of bleeding are worth studying.Objective The possible risk factors of esophageal variceal bleeding in in Chinese cirrhotic patients were observed in our current study to find the rule of variceal hemorrhage. Furthermore, we observed the relationships between the COMT gene polymorphism and the susceptibility to the patients with portal hypertension as well as the risk of esophageal variceal bleeding.Methods There were two hundred and two cirrhotic patients with esophageal varices, one hundred and two patients with esophageal variceal bleeding were considered as bleeding group and ninety patients without hemorrhage as non-bleeding group.The relationship between the clinical presentations and esophageal variceal bleeding was investigated by one-way analysis and Logistic regression mode. In addition, polymerase chain reaction-restriction fragment length polymorphism assay was used to identify the gene polymorphism of COMT of 104 cirrhotic patients and 140 healthy and unrelated individuals, then plasma catecholamines concentrations were detected in 74 of these patients by high performance liquid chromatography-eletrochemical detection to observe the relationships between the gene polymorphism and the concentrations. Moreover, we carried on one year follow-up study on the hemorrhage of patients.Results (1) Significant differences of course of disease, portal vein diameter, splenic vein diameter, splenic index, red color sign and classification of esophageal varice were found between bleeding group and non-bleeding group(P<0.05), prothrombin activity in rebleeding group was significantly lower than that in patients without rebleeding(P<0.01).Course of disease, prothrombin activity, red color sign were the risk factors of esophageal variceal bleeding in Logistic regression mode.(2)Plasma concentrations of norepinephrine significantly increased in cirrhotic patients with different Child-pugh classifications(P<0.05), while plasma epinephrine levels were not increased. Plasma norepinephrine concentrations were higher in cirrhotic patients with esophageal variceal bleeding than those without(P<0.05).(3) No significant differences were found in both genotype frequencies and allele frequencies between cases and controls(P>0.05). Furthermore, there were also no significant differences in both genotype frequencies and allele frequencies between patients with portal hypertension and those without(P>0.05).(4) Plasma norepinephrine concentrations(ng/ml)were 0.28±0.14,0.41±0.23, 0.76±0.16 in GG, GA and AA genotypes, respectively(P<0.05).Furthermore, plasma norepinephrine concentrations of GA plus AA genotypes were significantly higher than those of GG genotypes with the same Child-pugh classifications(P<0.05).(5) When stratified by esophageal variceal bleeding, the frequencies of GA plus AA genotypes and A allele in patients with esophageal variceal bleeding were higher than those without (46.7% vs 42.4%, 26.7% vs 24.6%), but could not reach significant differences. After one year follow-up study, the hemorrhage rate of patients with different genotypes that were not been treated was increased, but also could not reach significant differences in our current study(P>0.05).Conclusion Course of disease, prothrombin activity, red color sign were the major risk factors of esophageal variceal bleeding in patients with cirrhosis. There is the polymorphism in COMT gene in Chinese Anhui Han population, and the COMT A allele frequency is lower. No association can be found in the involvement of COMT gene polymorphism in the susceptibility to cirrhotic patients with portal hypertension as well as the risk of esophageal variceal bleeding, so further study is needed. Moreover, plasma norepinephrine concentrations are correlated with COMT gene polymorphism, this gene polymorphism may act together with plasma norepinephrine concentration for the development of cirrhosis.