Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis

Table 1 Part I (initiation) and II (perpetuation) of sinusoidal pressure hypothesis

SPH Part I: Initiation of a pro-fibrogenic response by elevated sinusoidal pressure

1. All liver diseases cause SP elevation. SP is the combined result of dynamic and static components that include the hepatic inflow/outflow balance, intra- and extrahepatic shunts as well as vascular filling by water retention and osmotic pressure.

2. LS represents the sum of matrix deposition (fibrosis) and SP. In non-cirrhotic livers, LS corresponds to SP.

3. Dosage and time of elevated SP/LS determine fibrosis progression (biomechanic signaling). Matrix deposition ultimately matches SP (force = counter force).

4. At the cellular level, SP elevation causes stretch forces on perisinusoidal cells that ultimately lead to collagen (matrix) deposition via inter- and intracellular biomechanic signaling.

SPH Part II: Continued pressure-elevation by arterialization of the fibrotic liver (perpetuation)

1. At a LS of ca. 12 kPa/SP of 12 mmHg, arterial blood supply becomes essential ultimately leading to arterialization of the liver (via hypoxia-signaling including HABR, VEGF etc.).

2. Arterial supply is ultimately not reversible causing loss of endothelial fenestrae, capillarization and sustained SP and LS elevation.

3. Arterialization initiates a vicious cycle leading to further matrix deposition, eventual complete disconnection of hepatocytes from blood supply and ischemia with subsequent arterialization and nodular regeneration.

4. Finally, the arterialized liver (high oxygen, high pressure) combined with cell death and enhanced regeneration will cause a pro-cancerogenic environment and HCC.

SPH: Sinusoidal pressure hypothesis; HABR: Hepatic arterial buffer response; HCC: Hepatocellular carcinoma; LS: Liver stiffness; SP: Sinusoidal pressure; VEGF: Vascular endothelial growth factor.