Serum Oxidative/anti-oxidative Stress Balance Is Dysregulated in Potentially Pulmonary Hypertensive Patients with Liver Cirrhosis: A Case Control Study

Abstract

Objective Hepatopulmonary syndrome (HPS) is characterized by vascular dilatation and hyperdynamic circulation, while portopulmonary hypertension (POPH) is characterized by vasoconstriction with fibrous obliteration of the vascular bed. Vasoactive molecules such as nitric oxide (NO) are candidate factors for cirrhotic complications associated with these diseases. However, oxidative stress balance is not well characterized in HPS and POPH. The present objective is to investigate the oxidative stress and anti-oxidative stress balance and NO pathway balance in patients with potential HPS and POPH. Methods We recruited patients with decompensated cirrhosis (n=69) admitted to our hospital as liver transplantation candidates. Patients exhibiting partial pressure of oxygen lower than 80 mmHg and alveolararterial oxygen gradient (AaDO2) ! 15 mmHg were categorized as potentially having HPS (23 of 69 patients). Patients exhibiting a tricuspid regurgitation pressure gradient ! 25 mmHg were categorized as potentially having POPH (29 of 61 patients). Serum reactive oxygen metabolites were measured and anti-oxidative OXYadsorbent test (OXY) were performed, and the balance of these tests was defined as the oxidative index. The correlation between these values and the clinical characteristics of the patients were assessed in a crosssectional study. Results Potential HPS patients exhibited no correlation with oxidative stress markers. Potential POPH patients exhibited lower OXY (p=0.037) and higher oxidative index values (p=0.001). Additionally, the vascular NO synthase enzyme inhibiting protein, asymmetric dimethylarginine, was higher in potential POPH patients (p=0.049). The potential POPH patients exhibited elevated AaDO2, suggesting the presence of pulmonary shunting. Conclusion Potential POPH patients exhibited elevated oxidative stress with decreased anti-oxidative function accompanied by inhibited NO production. Anti-oxidants represent a candidate treatment for potential POPH patients.

Impact of liver damage on blood-borne variables and pulmonary hemodynamic responses to hypoxia and hyperoxia in anesthetized rats

“…Furthermore, a low PaO 2 /FIO 2 ratio in the CBDL+PPVL group is verifying the injury of the blood gas barrier in the severe liver dysfunction. In both HPS and POPH, low PaO 2 and low saturation of hemoglobin with oxygen have been reported [6,7,[68][69][70]. On the other hand, low PaO 2 may lead to pulmonary vasoconstriction and explain partly increased RVSP in the CBDL+PPVL group (Table 2).…”

“…For instance, a few studies have shown that NO production increases in human cirrhosis [74,75], and NO plays a role in the regulation of pulmonary vascular tone in the animal model of cirrhosis [35]. In contrary, NO synthase inhibitor protein increases, thereby, NO production decreases in the cirrhotic patients [6,76]. However, we measured the plasma NO metabolites which could release from different sources in the body tissues.…”

“…The plasma concentration of MDA in the CBDL group was more than those in the sham and PPVL groups. Other investigators also have expressed that oxidants increase and antioxidants decrease in liver cirrhosis [6,71]. ROS may be involved in HPV [72].…”

“…On the other hand, pulmonary artery pressure increases in POPH as a consequence of pulmonary vasoconstriction and vascular remodeling [3][4][5]. Furthermore, the impairment of gas exchange may occur in POPH patients [6,7].…”

“…We previously indicated that ET-B receptors on the pulmonary smooth muscle cells play roles in the regulation of pulmonary vascular tone in animal model of liver cirrhosis [14]. Human studies have shown that reactive oxygen species (ROS) increase in POPH, but not in HPS [6,15], whereas, ROS are reportedly increased in animal models of HPS [7,[16][17][18]. Furthermore, high level of ROS may decrease the bioavailability of NO and lead to the constriction of pulmonary vessels [19].…”