Liver Cirrhosis And The Sinusoidal Pressure Hypothesis

The sinusoidal pressure hypothesis proposes elevated sinusoidal pressure as a driving force of fibrosis and cirrhosis rather than merely a consequence of advanced liver disease.

Inflammation, cellular swelling, congestion or impaired outflow can increase sinusoidal pressure and generate mechanical stretch within the perisinusoidal compartment. Mechanosignalling activates matrix-producing cells and promotes fibrosis.

The hypothesis provides the first mechanistic explanation for the ‘point of no return’ in liver cirrhosis. Progressive vascular resistance induces hepatic arterialization, permanently exposing the sinusoidal bed to arterial pressure. The resulting mechanical stretch sustains fibrotic matrix deposition even after the initial cause of liver injury has been removed, establishing a self-perpetuating cycle of cirrhosis.

It also explains why fundamentally different liver diseases converge on the same cirrhotic architecture: regardless of the initiating etiology, increased sinusoidal pressure produces similar mechanical forces and a common fibrotic response. Unlike previous molecular concepts, the hypothesis can account for the macroscopic formation of broad fibrous septa and the large-scale structural remodelling characteristic of the cirrhotic liver.

Selected publications

Liver stiffness is directly influenced by central venous pressure. Millonig G et al. J Hepatol. 2010;52(2):206–210.
Arterial pressure suffices to increase liver stiffness. Piecha F et al. Am J Physiol Gastrointest Liver Physiol. 2016;311(5):G945–G953.
Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis. Mueller S. World J Gastroenterol. 2016;22(48):10482–10501.
Pharmacological decrease of liver stiffness is pressure-related and predicts long-term clinical outcome. Piecha F et al. Am J Physiol Gastrointest Liver Physiol. 2018;315(4):G484–G494.