Effects Of Using Non Selective β-blockers In Patients With Portal Hypertension And Correlation Between The NAT2 Gene Polymorphism And Cirrhotic Portal Hypertension

BackgroundPortal hypertension (PH) is caused by increased resistance, increased blood flow, or both in the portal circulation. Then it causes a series significant clinical signs and symptoms. The portosystemic gradient is assessed by measuring the wedged hepatic venous pressure and subtracting the free hepatic venous pressure thus obtaining the hepatic venous pressure gradient (HVPG).A normal HVPG is 1-5 mmHg. An HVPG above 5 mmHg defines portal hypertension.. An HVPG of 10 mmHg or greater defines clinically significant portal hypertension as this pressure gradient predicts clinical course in patients with cirrhosis including development of varices, clinical decompensation including ascites, variceal hemorrhage and encephalopathy.In 1981, Lebrec et al performed the first randomized clinical trial involving 74 cirrhotic patients with a history of variceal bleeding. This study documented a significant reduction in rebleeding in patients on propranolol as compared to placebo. Since then, there were more and more studies on NSBB in portal hypertension patients. NSBB can improve not only on hemodynamic in cirrhosis patients with portal hypertension, but on non-hemodynamic.There is a decrease of HVPG by at least 20% of baseline or to values <12 mmHg. Patients achieving such a target reduction in portal pressure have been defined hemodynamic responders.The effect of propranolol on HVPG is variable, with up to 31% reduction reported. However, a third of patients do not have a hemodynamic response to propranolol. Carvedilol has been investigated as a promising NSBB with the additional property of vasodilatation due to its intrinsic anti-α1 adrenergic activity and its capacity to enhance the release of nitric oxide. A recent study also showed that carvedilol achieved a hemodynamic response in 56% of hemodynamic nonresponders to propranolol. The presence of beneficial effects of NSBB unrelated to their hemodynamic mechanism is also suggested by the fact that patients, even when "hemodynamic non responders", may have a reduced risk of bleeding while receiving NSBB.Several risk factors of portal vein thrombosis (PVT) in liver cirrhosis have been established. The most important risk factor is decreased portal inflow velocity in liver cirrhosis developing PVT.Studies have illustrated that genetic susceptibility played an essential role in the occurrence and development of cirrhotic portal hypertension and family aggregation tendency can be commonly seen in some patients.N-acetyltransferase 2 (NAT2), as a highly polymorphic enzyme, was reported to be associated with cirrhotic portal hypertension.Recent study has suggested that the NAT2 gene was involved in the formation of cirrhotic portal hypertension, while there were few studies reported the relationship between the polymorphism of NAT2 gene of each site and cirrhotic portal hypertension.In this study, we observed the effects of hemodynamic and non-hemodynamic in decompensated cirrhosis patients using propranolol or carvedilol. We investigate the relationship between portal blood flow velocity and hemodynamic or non-hemodynamic. Further explore security of NSBB in decompensated cirrhosis with with refractory ascites. And our study aims to discuss the correlation between NAT2 gene polymorphism and cirrhotic portal hypertension in Chinese population, for the purpose of seeking for the risk factors for the formation of cirrhotic portal hypertension from the perspective of gene, further to explore the functional significance of NAT2 gene polymorphism.Part I:Hemodynamic and non-hemodynamic effests of using non selective β-blockers in depcompensation cirrhotic patients[Objective] Study the effects of NSBB in hemodynamics and non hemodynamic with using propranolol or carvedilol in decompensated cirrhosis. And explore the effects and safety of NSBB in decompensated cirrhosis patients with massive ascites.[Methods] Methods All patients of propranolol group (42) and carvedilol group (54) received a series of tests including blood routine test, liver and kidney function, blood coagulation system, abdominal ultrasound, abdominal CT and computed tomography portal venography. After all patients underwent first HVPG measurement, the patients of propranolol group were given propranolol (10 mg Po, tid), and the patients of carvedilol group were given carvedilol (12.5 mg Po, qd). At 1 week,1 month and 3 months after administration, all patients received blood routine test, liver and kidney function, blood coagulation system and abdominal color Doppler examination.[Results]1. The mean times of EVL+EIS occurred in the patients of propranolol group were 1.45 ± 0.97, and 1.48 ± 1.09 in carvedilol group, with no significant difference between 2 groups (P=0.892). In the follow-up time of 6 months, no variceal bleeding occurred in 2 groups. The follow-up time of 31 patients in propranolol group was more than 24 months,8 patients underwent variceal bleeding, The follow-up time of 35 patients in carvedilol group was more than 24 months,4 patients underwent variceal bleeding, there was no no significant difference between propranolol group and carvedilol group (P=0.233).2.96 patients with decompensated cirrhosis were treated with propranolol and carvedilol. Propranolol group patients were measured HVPG 13.64±2.81 mmHg, and carvedilol group patients were measured HVPG 12.51±2.95mmHg at 1 week.There was no significant difference in HVPG between 2 groups (P>0.05). Propranolol group patients were measured HVPG 11.37±2.35 mmHg, and carvedilol group patients were measured HVPG 10.03±2.69 mmHg at 1 month. There was a signifancent difference between 2 groups (P=0.012). Propranolol group patients were measured HVPG11.27±2.17 mmHg, and carvedilol group patients were measured HVPG 9.98±2.61mmHg at 3 month. There was a significant difference e between 2 groups (P=0.010).3. In propranolol group and carvedilol group, the HVPG of patients were significantly reduced at 1 week after administration (P<0.001).The HVPG of patients at 1 month after administration were significantly reduced compared with the one at lweek after administration(P<0.001). The HVPG of patients at 3 months after administration were not significantly reduced compared with the one at 1 month after administration (Propranolol group P=0.140, Carvedilol group P=0.146).4. In the follow-up time of 3 months, the number of patients of non-response to medicine was 10 (23.8%)in propranolol group, and 3(5.6%) in carvedilol group, with significant difference between propranolol group and carvedilol group (P=0.022). 5. The follow-up time of 31 patients in propranolol group was more than 24 months, the ascites of 21 patients were significantly reduced, the ascites of 4 patients were disappeared, the ascites of 2 patients were significantly increased because of portal vein thrombosis. The follow-up time of 35 patients in carvedilol group was more than 24 months, the ascites of 23 patients were significantly reduced, the ascites of 5 patients were disappeared, the ascites of 1 patients were significantly increased because of portal vein thrombosis; For the treatment of ascites, there was no significant difference between propranolol group and carvedilol group (P=0.715).[Conclusion]1. Propranolol or carvedilol can effectively reduce the HVPG of patients with decompensated cirrhosis, the effectiveness of each medicines achieves stable state at 1 month after administration.2. Propranolol or carvedilol can effectively prevent varices bleeding of patients with decompensated cirrhosis.3. Carvedilol can more effectively reduce the HVPG than propranolol;4. Propranolol or carvedilol can effectively control the development of ascites in patients with decompensated cirrhosis. And both are safe and effective in cirrhosis patients with middle - a lot ascites.Part Ⅱ Hemodynamic effests of using propranolol between propranolol responders and non-responders[Objective] Treat the patients with decompensated cirrhosis using propranolol, then evaluate the change of blood velocity of the patients who respond to propranolol or non-respond to propranolol, and explore their risks of development PVT.[Method] 28 patients had none portal vein thrombosis(none PVT group) and 12 patients had portal vein thrombosis(PVT group). All patients of response to propranolol group (PI group,22), non-response to propranolol group (P2 group,6) and portal vein thrombosis group (T group,12) received a series of tests including blood routine test, liver and kidney function, blood coagulation system, abdominal ultrasound. The patients of P1 group and P2 group were given propranolol (10 mg Po, tid) after the first HVPG measurement, At 1 month after administration, All patients received HVPG, abdominal ultrasound, blood routine test, liver and kidney function tests.[Results]1. PT of none PVT group was 14.86±1.26s and that of PTV group was 15.87±1.27s. Hb of none PVT group was89.64±21.01g/L and that of PVT group was 75.50±13.39g/L. PLT of none PVT group was 93.32±15.42 x109/L and that of PVT group was 72.33±17.63 x109/L. TBIL of none PVT group was 34.89±11.84 mmol/1 and that of PVT group was 48.48± 14.32 mmol/1. Portal vein diameter of none PVT group was 1.51 ±0.21cm and that of PTV group was 1.68±0.19cm. Portal vein blood velocity of none PVT group was 11.26±1.89cm/s and that of PTV group was 9.34±1.46cm/s. Child-Pugh score of none PVT group was 6.89±1.50 and that of PTV group was 8.83±1.53. There were significant difference in PT% Hb、PLT、 TBIL、 portal vein diameter、 portal vein blood velocity and Child-Pugh score between none PVT group and PVT group(P<0.05).2. Before administration, the HVPG of P1 group and P2 group is 17.55±3.56mmHg and 16.50±2.88mmHg respectively. There was no significant difference between 2 groups (P= 0.515). After administration, the HVPG of P1 group and P2 group is 10.50±1.80mmHg and 15.01 ± 1.90mmHg respectively. There was a significant difference between 2 groups (P<0.001).3. In P1 group, the portal vein diameter reduced remarkably after administration (P <0.001). In P2 group, the portal vein diameter reduced after administration too, but there was no signifencant difference (P=0.184).4. In P1 group, the portal vein blood velocity reduced remarkably after administration (P=0.032). In P2 group, the portal vein blood velocity reduced too after administration, but there was no signifencant difference (P-0.468).5. There was a negative correlation between the portal vein diameter and portal vein blood velocity in all groups (r=-0.851, P<0.001).There was a negative correlation between the Child-Pugh score and portal vein blood velocity in all groups (r=-0.719, P<0.001).[Conclusions]1. The portal vein blood velocity of patients of decompensated cirrhosis with portal vein thrombosis lowered significantly than without portal vein thrombosis.2. The portal vein blood velocity of patients responding to propranolol reduced remarkably, this may cause the portal vein thrombosis.3. There was a negative correlation between the portal vein diameter and portal vein blood velocity or Child-Pugh score and portal vein blood velocity.Part III Correlation between the NAT2 Gene Polymorphism and Cirrhotic Portal Hypertension[Objective] Our study aims to discuss the correlation between NAT2 gene polymorphism and cirrhotic portal hypertension in Chinese population, for the purpose of exploring the functional significance of NAT2 gene polymorphism.[Method] From June 2010 to February 2014, a total of 212 post-hepatitis B cirrhosis patients (the observation group) diagnosed by needle biopsy of liver, B ultrasound or surgical operation were recruited. These 212 patients were divided into cirrhotic portal hypertension group (PHT+ group) (130 patients) and simple liver cirrhosis (LC) group (PHT group) (82 patients), and 172 healthy blood donors were enrolled into the control group. The PCR-RFLP method was adopted to detect NAT2 gene polymorphism and some related statistics analysis.[Results]1. In these 212 patients, four mutation alleles in the NAT2 gene (WT, Ml, M2 and M3) were detected. The NAT2 rapid acetylator genotypes possessed WT/WT, WT/M1, WT/M2 and WT/M3, and the NAT2 slow acetylator genotypes contained M1/M1, M1/M2, M1/M3, M2/M2, M2/M3 and M3/M3. The frequency of patients carrying NAT2 slow acetylator genotype in the observation group was higher than that in the control group, but there was no significant difference (13.21% �'� 8.80%, P＞ 0.05).2. There was significant difference in the NAT2 slow acetylator genotype frequency between the PHT+ group and the control group (14.62% �'� 8.80%, P<0.05).3. The risk for the occurrence of PHT in NAT2 slow acetylator genotype carriers was more frequent than that in NAT2 rapid acetylator genotype carriers (OR= 2.2,95% CI:0.18～5.34, R=0.16)[Conclusion] Our study provided empirical evidence that NAT2 gene polymorphism may be correlated to the formation of cirrhotic portal hypertension, and it might be used as potential biomarkers for genetic susceptibility of PHT in Chinese population.