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.

Table 2 Potential studies to elucidate sinusoidal pressure-mediated mechanisms of fibrosis

Potential studies to validate SPH
1. Matrix-modulating effects of pressure-lowering or modulating drugs.
2. Physical aspects of pressure formation in biological tissues including the role of cardiac pulse wave energy and its mechanic absorption by fat.
3. Effect of water metabolism, water channels (aquaporins), electrolyte transporters and other transporters and osmotic pressure on matrix formation.
4. Role of pressure-mediated biomechanic signaling for matrix formation including genetics, proteomics and metabolomics.
5. Role of ECM, cellular and inter-cellular junctions on pressure-mediated matrix formation.
6. Role of SP on gap junctions and matrix formation[78].
7. Role of vasoactive systems/substances, such as nitric oxide, cyclooxygenase-derivatives, carbon monoxide and endogenous cannabinoids on SP and fibrosis[79].
8. Role of vasoconstrictor systems, such as the sympathetic nervous system, vasopressin, angiotensin and endothelin-1 on SP and fibrosis[80,81].
9. Optimization of pressure sensors e.g., for the liver sinus including the development of molecular stretch force measuring sensors[4].
10. Association of pressure, tissue/cellular stiffness and matrix formation at various organizational levels (cell, organ and whole organism).
11. Interplay of organ systems involved in water and pressure regulation (e.g., heart, brain, kidney and liver) for pressure regulation and matrix development.
12. Role of liver size and globularization of liver in various species in order to better sustain stretch forces of SP elevation.
13. Mechanisms and modulation of vessel and shunt formation in the liver.

ECM: Extracellular matrix; SP: Sinusoidal pressure; SPH: Sinusoidal pressure hypothesis.

Table 3 Direct clinical consequences of sinusoidal pressure hypothesis

Potential clinical impact of SPH	Ref.
1. Therapeutic effects of pressure lowering drugs. Optimization of timing, patient selection, dosage and duration. Risk balancing of side affects to other organs (kidneys, arterial underfilling).	[77]
2. Long-term therapy with diuretics as causal/fibrosis-blocking treatment.
3. Testing of an optimized risk stratification of cirrhotics on outcome according to liver stiffness (M1 vs M2 type, see paragraph "Important consequences of SPH and critical discussion", point 3) in addition to liver function scores such as Child-Pugh score or MELD score.	[25]
4. Liver disease as cause and consequence in the systemic context with other organs such as kidney and heart failure.	[57]
5. Test whether GGT elevation and an AST/ALT ratio > 1 at low AST and ALT levels is related with arterialization of liver and, consequently, with manifestation of liver cirrhosis.
6. Study water retention in cirrhosis, pregnancy, renal and heart failure and its consequences on hydrostatic SP.	[82]
7. Implementation of osmotic stress, water channels (aquaporines) and transporters.
8. Therapeutic approaches to lower SP by targeting mechano-signaling: mechanic conditioning and pharmacotherapy acting on mechano-signaling.
9. Role of biomembrane composition, lipid composition and potential protective role of steatosis on pressure-induced fibrosis.
10. Non-invasive LS measurements to monitor and optimize treatment of liver diseases.
11. Implementation of liquid physics to better understand the dynamic component of SP and its role on fibrosis progression.
12. Understanding of pulse wave energy and its consequences on the liver tissue.

ALT: Alanine aminotransferase; AST: Asparagin aminotransferase; GGT: Gamma-glutamyl transpeptidase; LS: Liver stiffness; SP: Sinusoidal pressure; SPH: Sinusoidal pressure hypothesis.