5-MTHF enhances the portal pressure reduction achieved with propranolol in patients with cirrhosis: A randomized placebo-controlled trial.

Vukotic, Ranka; Di Donato, Roberto; Roncarati, Greta; Simoni, Patrizia; Renzulli, Matteo; Gitto, Stefano; Schepis, Filippo; Villa, Erica; Berzigotti, Annalisa; Bosch, Jaume; Andreone, Pietro (2023). 5-MTHF enhances the portal pressure reduction achieved with propranolol in patients with cirrhosis: A randomized placebo-controlled trial. Journal of hepatology, 79(4), pp. 977-988. Elsevier 10.1016/j.jhep.2023.06.017

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BACKGROUND AND AIMS

β-blockers reduce hepatic venous pressure gradient (HVPG) by decreasing portal inflow, with no reduction of intrahepatic vascular resistance. 5-Methyltetrahydrofolate (5-MTHF) can prevent oxidative loss of tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS) coupling. It also converts homocysteine (tHcy) in methionine and enables the degradation of asymmetric dimethylarginine (ADMA), an inhibitor of eNOS. The aim of this study was to evaluate the effects of 5-MTHF in combination with propranolol on HVPG and nitric oxide (NO) bioavailability markers in patients with cirrhosis and portal hypertension (PH).

METHOD

Sixty patients with cirrhosis and HVPG ≥12mmHg were randomized 1:1 to receive treatment with 5-MTHF+propranolol or placebo+propranolol for 90 days under double-blind conditions. HVPG and markers of NO bioavailability BH4, ADMA and tHcy were measured again at end of treatment.

RESULTS

Groups were similar in baseline clinical and hemodynamic data and NO-bioavailability markers. HVPG decreased in both groups, but the magnitude of the change was significantly greater in the group treated with 5-MTHF+propranolol compared to placebo+propranolol (percent decrease, 20 [29-9] vs 12.5 [22-0], p=0.028), without differences in liver blood flow. At the end of treatment, 5-MTHF+propranolol group compared to placebo+propranolol group showed higher BH4 (pg/mL, 1101.4±1413.3 vs 517.1±242.8, p<0.001), lower ADMA (μmol/L, 109.3±52.7 vs 139.9±46.7, p=0.027) and lower tHcy (μmol/L, 11.0±4.6 vs 15.4±7.2, p=0.010) plasma levels.

CONCLUSION

In patients with cirrhosis and portal hypertension, 5-MTHF administration significantly enhanced the HVPG reduction achieved with propranolol. This effect appears to be mediated by an improved NO bioavailability in liver microcirculation.

IMPACT AND IMPLICATIONS

Currently, the pharmacological prevention of cirrhosis complications due to portal hypertension, as esophageal varices rupture, is based on the use of β-blockers, but some patients still present acute variceal bleeding, mainly due to an insufficient reduction of portal pressure. In this study, we sought to demonstrate that the addition of folic acid to β-blockers is more effective in reducing portal pressure than β-blockers alone. This finding could represent a basis for validation studies in larger cohorts to potentially impact the future management of pharmacological prophylaxis of variceal bleeding in cirrhosis. Enhancing the benefit of β-blockers by a safe, accessible, cost-effective drug could improve clinical outcomes in cirrhosis which in turn could translate in a reduction of rates and costs of hospitalization, ultimately ameliorating survival. Clinical trial EudraCT number 2014-002018-21.

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