Role of Sinusoidal Pressure and Arterialization in Driving Fibrosis Progression

Abstract

The Sinusoidal Pressure Hypothesis (SPH) has been recently introduced which identifies an elevation of sinusoidal pressure (SP) as cause of fibrosis and liver cirrhosis. Normally, pressure changes in the context of cirrhosis are associated with portal hypertension which is a consequence of cirrhosis. According to the SPH, however, an elevated SP is the major upstream event that initiates fibrosis (initiation). In healthy liver, liver stiffness (LS) corresponds to SP and increases in response to many pro-fibrogenic stimuli such as inflammation, cholestasis, or liver congestion. SPH postulates that extracellular matrix is produced in response to elevated SP to withstand the underlying pressure. Both duration (>4 weeks) and degree (>12 mmHg or >12 kPa) of SP/LS elevation are critical. While fibrosis can still reverse if the underlying cause of SP elevation is eliminated, the increased matrix deposition causes an increasing blood supply through the hepatic artery. This elevated hepatic arterial flow and the final arterialization of the liver permanently cause pathologically high pressures. A vicious cycle is initiated with further matrix deposition and increased arterial pressure. Thus, arterialization defines the so-called “point of no return” with irreversible fibrosis progression. At the cellular level, SP is the actual driving force for the production of collagen by stretching of perisinusoidal cells, pressure-related increase in tissue stiffness, and stretch forces transduced via cellular and intercellular biomechanic signaling. SPH is able to explain the macroscopic changes of the cirrhotic liver (trajectory forces), the uniform fibrotic response to various etiologies, and the point of no return in advanced stages despite elimination of the cause. According to SPH, future treatment options should be targeted at lowering the sinusoidal pressure.