The role of nitric oxide in chronic liver disease

Nitric oxide (NO) regulates hepatic and systemic vascular tone. Abnormal NO distribution is a hallmark of portal hypertension. Under normal portal pressure, liver sinusoidal endothelial cells (LSECs) produce NO, promoting vasodilation and hepatic stellate cell (HSC) relaxation. In portal hypertension, endothelial dysfunction, asymmetric dimethylarginine (ADMA) imbalance, and superoxide impair intrahepatic NO availability, causing HSC activation and worsening portal hypertension. Excess splanchnic NO causes systemic vasodilation, hyperdynamic circulation, and collateral formation. Abnormal NO clearance contributes to hepatorenal syndrome (HRS) and hepatopulmonary syndrome (HPS). Statins, PDE‑5 inhibitors, and midodrine restore NO homeostasis with partial success.

Introduction

NO is generated enzymatically by nitric oxide synthases (nNOS, iNOS, eNOS) and non‑enzymatically. In hepatic circulation, eNOS is expressed in LSECs; eNOS‑derived NO is protective, whereas iNOS‑derived NO contributes to nitrosative stress via peroxynitrite. In cirrhosis, increased portal resistance and splanchnic NO production lead to vasodilation, gut bacterial translocation, and further vasodilation. Decreased effective arterial volume activates RAAS and sympathetic nervous system, increasing cardiac output and worsening portal hypertension. Portosystemic collaterals develop, leading to pulmonary and renal complications.

Normal NO Homeostasis

Shear stress upregulates KLF2, activating eNOS, which produces NO from L‑arginine. NO activates soluble guanylate cyclase (sGC), producing cGMP, causing sinusoidal vasodilation. cGMP activates PDE‑5, which degrades cGMP, self‑regulating NO's effect. NO is oxidised to nitrate/nitrite and eliminated by kidneys (~65% of oral nitrate excreted in urine); haemoglobin also scavenges NO.

Derangements of NO Homeostasis

Abnormal intrahepatic NO production: Portal hypertension induces shear stress and inflammation, activating xanthine oxidase and cyclooxygenase‑1, increasing superoxide. Superoxide reacts with NO to form peroxynitrite, decreasing NO bioavailability. Loss of NO reduces cGMP‑mediated vasodilation, increasing sinusoidal vasoconstriction. Activated HSCs contract, further increasing resistance.

ADMA: ADMA is an endogenous eNOS inhibitor. DDAH1 degrades ADMA; in cirrhosis, DDAH1 expression is reduced. ADMA levels are ~10× higher in end‑stage liver disease and correlate with HVPG and negatively with NO.

Shunting of NO: Portosystemic collaterals develop at portal pressures >8–10 mmHg, diverting blood away from the liver and decreasing intrahepatic NO.

Splanchnic NO production: Shear stress and inflammation drive intestinal VEGF expression, triggering eNOS activation and collateralisation.

Renal microcirculation: Plasma NO metabolites rise with worsening renal function, highest in HRS. NO negatively correlates with GFR.

Pulmonary circulation: HPS results from intrapulmonary vasodilation linked to increased NO, affecting ~30% of cirrhosis patients. Increased pulmonary endothelin stimulates eNOS, causing vasodilation and hypoxaemia.

Therapeutic Approaches

PDE‑5 inhibitors: Block cGMP conversion, prolonging NO vasodilation. Udenafil reduced HVPG by 15.7%. Sildenafil increased hepatic venous NO levels with favourable short‑term safety.

Statins: Induce NO production via eNOS stimulation mediated by KLF2. Simvastatin reduced HVPG (−5.9%) without systemic haemodynamic effects; NO product levels increased in hepatic venous blood.

Midodrine: An alpha‑adrenergic vasoconstrictor; decreased serum nitrite/nitrate and increased mean arterial pressure. However, a multicentre RCT found no significant difference in complications or one‑year mortality.

TIPS: Diverts portal blood to systemic vasculature. Systemic NO production increased post‑TIPS due to endotoxaemia. ADMA levels increased, and renal function improved in patients with pre‑TIPS renal dysfunction. Meta‑analyses show decreased 1‑year mortality and rebleeding, though HE risk is increased.

Conclusions

eNOS‑derived NO is protective; iNOS‑derived NO causes damage. Treatment should increase intrahepatic NO to reduce portal pressure while decreasing systemic NO. Simvastatin increases intrahepatic NO but carries risks. Midodrine improves NO bioavailability and MAP. PDE‑5 inhibitors appear safe but require further study. TIPS improves systemic blood pressure and long‑term survival in patients with good liver function, though HE risk remains. Larger randomised controlled studies are needed.

Full text

https://www.xiahepublishing.com/2310-8819/JCTH-2026-00173

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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